Benzimidazole derivatives, a process for their manufacture and use as a medicine

ABSTRACT

The invention concerns benzimidazole derivatives of the general formula (I)  
                 
 
     in which the radicals R 1 , R 2 , R 3 , X 1  and A can have the meanings assigned to them in the specification, their prodrugs, processes for their production as well as the use of the benzimidazole derivatives as medicines, especially as medicines that have trypsin-inhibiting action.

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application Serial No. 60/332,978,filed on Nov. 14, 2001 is hereby claimed, and said provisionalapplication is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to benzimidazole derivatives of theformula (I)

[0003] in which the residues X¹, R¹, R², R³ and A have the meaningsascribed to them in the Claims and in the text, to processes for theirproduction as well as to the use of benzimidazole derivatives asmedicines, especially as medicines having a tryptase-inhibiting action.

BACKGROUND OF THE INVENTION

[0004] Benzimidazole derivatives, as active substances that havevaluable pharmaceutical properties, are known in the prior art. Thus,the international patent application WO 98/37075 refers to benzimidazoleamongst other bicyclic heterocyclic compounds which, because of theirthrombin-inhibiting action, can be effectively administered for theprevention and treatment of venous and arterial thrombotic illnesses.

[0005] In addition, the international patent application WO 01/14342proposes the use of similar benzimidazole-5-yl-carboxamides havingtryptase-inhibiting action, which, however, do not contain a cyclicalamine of the formula:

[0006] The present invention has its object to make available newtryptase inhibitors with improved tryptase-inhibiting properties, thatcan be administered for the prevention and treatment of inflammatoryand/or allergic illnesses.

DETAILED DESCRIPTION OF THE INVENTION

[0007] Surprisingly, it was discovered that benzimidazole derivatives ofthe formula (I), in which X¹, R¹, R², R³ and A have the meaningsascribed to them below, have a higher tryptase-inhibiting action andcan, according to the invention, be used for the prevention andtreatment of illnesses in which tryptose-inhibitors can be oftherapeutic value.

[0008] The present invention, therefore, relates to benzimidazolederivatives of the formula (I)

[0009] in which

[0010] R¹ represents a C₁-C₁₀-Alkyl- or C₃-C₆-cyclo-alkyl-group thatcan, whenever required, be substituted once, twice or three times by oneor more of the groups comprising C₁-C₄-alkoxy, phenoxy, hydroxy-phenoxy,C₁-C₄-alkoxy-phenoxy, C₃-C₆-cyclo-alkyl, —NH₂, NH—(C₁-C₄-alkyl),—N(C₁-C₄-alkyl)₂, —NH—CO—(C₁-C₄-Alkyl), —CO—NH₂, —CO—NH—(C₁-C₄-alkyl) or—NH—CO-benzyl, or represents a phenyl-C₁-C₄-alkyl group in which thephenyl ring can, if necessary, be substituted once, twice or three timesby one or more of the C₁-C₄-alkyl , CF₃, fluorine, chlorine, bromine,COOH or COO—C₁-C₄-alkyl groups, or represents a 5-, 6- or 7-membered,saturated or unsaturated heterocyclic group that is linked via a singlebond or via a C₁-C₄-alkylene bridge, and that contains one, two or threeheteroatoms selected from oxygen, nitrogen and sulphur, and which may beoptionally substituted once, twice or three times by any one or more ofthe following radicals: C₁-C₄-alkyl, phenyl optionally substituted byC₁-C₄-alkyl, or benzyl optionally substituted by C₁-C₄-alkyl; or

[0011] said 5-, 6- or 7-membered, saturated or unsaturated heterocyclicgroup is optionally condensed via two adjacent carbon atoms with abenzene ring;

[0012] R² represents —C(═NH)NH₂ or —CH₂—NH₂;

[0013] X¹ represents —CO—;

[0014] A represents a 4- or 7-membered, saturated heterocyclic groupthat can contain one or two nitrogen atoms and, if required, one or twohetero-atoms selected from the group comprising oxygen and sulphur;

[0015] R³ represents a radical selected from the groups (a), (b) and(c):

[0016] (a) —NR⁴R⁵;

[0017] in which

[0018] R⁴ represents hydrogen or a residue having the formula

B—(CH₂)_(r)—X²—

[0019]  in which

[0020] B is C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₈-cycloalkyl, phenyl, naphthyl or a 5- or6-membered nitrogen-, oxygen- and/or sulphur-containing heterocyclicgroup, whereby in each case the phenyl, naphthyl or heterocyclic groupcan be substituted by one or more Groups selected from halogen, nitro,cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-alkyl-SO₂—,C₁-C₄-alkyl-PO₂—O—, C₁-C₅-alkanoyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, C₁-C₄-haloalkylthio,C₁-C₄-cyanoalkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, carboxy,amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)-amino, aminosulfonyl, phenyland hydroxy groups, or represents a phenyl group in which twoneighbouring carbon atoms are substituted by a C₁-C₄-alkylene-dioxygroup;

[0021] X² is CO, NH—CO, SO₂, NH—SO₂ or a single bond, and

[0022] r is 0 or a whole number from 1 and 4

[0023] R⁵ represents hydrogen or a residue having the formula:

D—(CH₂)_(t)—

[0024]  in which

[0025] D is C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₈-cycloalkyl, phenyl, naphthyl or a 5- or6-member nitrogen-, oxygen- and/or a heterocyclic group, in which eachof the phenyl, naphthyl or heterocyclic groups can be replaced by one ormore groups selected from halogen, nitro, cyano, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-alkyl-SO₂—, C₁-C₄-alkyl-PO₂—O—,C₁-C₅-alkanoyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-haloalkylthio, C₁-C₄-cyanoalkyl, C₁-C₄-hydroxyalkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, carboxy, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)-amino, aminosulfonyl, phenyl und hydroxy, or

[0026] is a phenyl group in which two neighbouring carbon atoms aresubstituted by a C₁-C₄-alkylene-dioxy-group, and

[0027] t is 0 or a whole number from 1 to 4, or

[0028] R⁴ and R⁵ together with the nitrogen atom form a 4- to10-membered, saturated heterocyclic group or spiro-heterocyclic group,which can optionally contain a further hetero atom selected from oxygen,nitrogen and sulphur, in which one or two CH₂ groups can be replaced byC═O or C═S, and which may be substituted by any one or more of theradicals selected from: C₁-C₄-alkyl, C₃-C₈-cycloalkyl, benzyl optionallysubstituted by C₁-C₄-alkyl, pyridyl and phenyl optionally substituted byC₁-C₄-alkyl, C₁-C₄-alkoxy or hydroxy;

[0029] (b) —E-phenyl, in which E represents —CH₂CH₂— or —CH═CH—;

[0030] (c) phenyl, which is substituted by one or more substituentsselected from the group comprising halogen atoms, trifluoro-methylgroups and nitro groups; if required, in the form of their tautomers,their racemates, their enantiomers, their dia-stereomeres and mixturesthereof, as well as, if required, their pharmacologicallyunobjectionable acid-addition salts.

[0031] The alkyl groups considered for use (including those that arecomponents of other radicals, especially of alkoxy), may, unlessotherwise defined, be branched or unbranched alkyl-groups having from 1to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to6 carbon atoms, especially having 1 to 4 carbon atoms. These may, forexample, be methyl, ethyl, propyl, butyl, pentyl, hexyl etc. groups.Unless otherwise indicated, the aforesaid definitions include, forexample, any of their possible isomeric forms. For example, thedefinition propyl includes the isomeric radicals n-propyl andiso-propyl, the definition butyl includes n-butyl, iso-butyl, sec.butyland tert.butyl, the definition pentyl includes iso-pentyl, neo-pentyletc. If required, the definitions of the afore-mentioned alkyl groupscan also be identified by their abbreviations such as Me for methyl, Etfor ethyl etc.

[0032] The halo-alkyl groups considered for use (also where they arecomponents of other radicals, especially of haloalkoxy groups) are,unless otherwise defined, branched or un-branched halo-alkyl groupshaving 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, morepreferably having 1 to 3 carbon atoms, that are substituted by at leastone halogen atom, especially the fluorine atom. These are preferablyfluorinated radicals having the formula

—(CH₂)_(p)—(CF₂)_(q)—Y

[0033] in which

[0034] p is 0 or a whole number from 1 to 4,

[0035] q is a whole number from 1 to 4, and

[0036] Y represents hydrogen or fluorine.

[0037] These are, for example, trifluoro-methyl, trifluoro-methoxy,difluoro-methyl, difluoro-methoxy, perfluoro-ethyl,2,2,2-trifluoro-ethyl, 2,2,2-trifluoro-ethoxy,1,1,1-trifluoro-prop-2-yl, etc.

[0038] The alkenyl groups used (also as components of other radicals)are branched or un-branched alkenyl groups having 2 to 12 carbon atoms,preferably 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, so longas they contain at least one double bond, also, for example, theabove-mentioned alkyl groups so long as they contain at least one doublebond, such, for example, as vinyl (as long as no unstable enamine orenolether is formed), propenyl, iso-propenyl, butenyl, pentenyl,hexenyl.

[0039] The alkynyl; groups used (also as components of other radicals)are alkynyl groups having 2 to 12 carbon atoms, preferably 2 to 6 carbonatoms, especially 2 to 4 carbon atoms, so long as they contain at leastone triple bond, such, for example, as ethinyl, propargyl, butinyl,pentinyl, hexinyl.

[0040] The halogen used is generally fluorine, chlorine, bromine oriodine.

[0041] The expression “5- or 6- or 7-membered nitrogen-, oxygen-, and/orsulphur-containing heterocyclic groups” as used in the R¹, B or Dradicals, generally refers to an aromatic or saturated radical having 5,6 or 7 atoms in the ring, in which at least one ring atom is ahetero-atom selected from the group N, O and S, which can, if required,be condensed with a further ring system.

[0042] The expression “4- to 10-membered heterocyclic group” as used inA and, together with the enclosed nitrogen atom, for the R⁵ and R⁶,generally refers to a saturated nitrogen-containing radical that has 4to 10, preferably 5 to 7 atoms in the ring, which, if required, may alsohave one or more hetero-atoms selected from the group N, O and S, andwhich may, if required, be condensed with a further ring system.

[0043] The expression “spiro-heterocyclic group” as used for the groupsthat, together with the enclosed nitrogen atom, form the R⁵ and R⁶,generally refers to a saturated nitrogen-containing radical having 8 to11, preferably 9 to 10 ring atoms, which, if required, can also containone or two hetero-atoms from the group N, 0 and S, and in which one ortwo CH₂ groups can be replaced by C═O or C═S. Preferredspiro-hetero-cyclic groups are azaspiro[4,4]-nonane,azaspiro[5,4]-decane and azaspiro[5,5]-undecane, especially2,4-dioxo-1-oxa-3-aza-spiro[4,4]-nonane.

[0044] The preferred heterocyclic groups are, for example, acridinyl,acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl,azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl,azaindolyl, azanaphthacenyl, azanaphthalenyl, azaprenyl,azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl, benzacridinyl,benzazapinyl, benzofuryl, benzonaphthyridinyl, benzopyranonyl,benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl,benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl,butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl,chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl,decahydroquinolinyl, decahydroquinolonyl, diazaanthracenyl,diazaphenanthrenyl, dibenzazapinyl, dibenzofuranyl, dibenzothiphenyl,dichromylenyl, dihydrofuranyl, dihydroisocumarinyl,dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl,dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl,dioxanthylenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl,fluoresceinyl, furandionyl, furanochromanyl, furanonyl,furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl,hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl,hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl,hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl,indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl,isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl,isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl,lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl,naphthimidazopyridindionyl, naphthindolizinedionyl,naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl,oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl,phenanthrachinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl,piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl,pyranoazolyl, pyranopyrandionyl, pyranopyridinyl, pyranochinolinyl,pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinethionyl,pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl,pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl,pyridoquinolinyl, pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl,pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl, pyrrolopyrimidinyl,pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolinyl, quinolizidinyl,quinolizinyl, quinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl,succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl,tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl,thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl,thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl,thiepinyl, thiochromenyl, thiocumarinyl, thiopyranyl, triazaanthracenyl,triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl,xanthydrolyl, adeninyl, alloxanyl, alloxazinyl, anthranilyl,azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azaphenoxazinyl,azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl,benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl,benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl;benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl,benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl,cinnolinyl, depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl,dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl,dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl,dihydrothiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl,dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl,dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl,glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl,hexahydropyridazinyl, hydantoinyl, hydroimidazolyl, hydroparazinyl,hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl,imidazolyl, imidazoquinazolinyl, imidazothiazolyl,indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl,isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl,isoxazolonyl. isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl,morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl,oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl,oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl,perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl,perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl,piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl,pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl,pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl,pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl,pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl,pyrimidinyl, pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl,pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl,quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl,sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl,tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl,thiazepinyl, thiazinyl, thiazolidinonyl, thiazolidinyl, thiazolinonyl,thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl,thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl,xylitolyl, azabenzonapththenyl, benzofuroxanyl, benzothiadiazinyl,benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl, dioxadiazinyl,dithiadazolyl, dithiazolyl, furazanyl, furoxanyl, hydrotriazolyl,hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxathiazinonyl, oxatriazolyl,pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl,tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl,thiadiazolinyl, thiadiazolyl, thiadioxazinyl, thiatriazinyl,thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl,triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl,triphenodithiazinyl, trithiadiazepinyl, trithianyl or trioxolanyl.

[0045] Especially favourable are the 5-, 6- or 7-member, saturated orunsaturated heterocyclic groups, that can contain the hetero-atomsnitrogen, oxygen or sulphur, as long as they are not otherwise describedin the definition, such, for example, as pyrrole, pyrroline,pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline,imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine,pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine,thiomorpholine, diazepane, oxazole, isoxazole, oxazine, thiazole,isothiazole, thiadiazole, oxadiazole, pyrazolidine, in which theheterocyclic.group can be substituted as indicated in the definitions.

[0046] The favoured compounds are those of the formula 1, in which R¹,R², A and X¹ have the afore-mentioned definitions, and

[0047] R³ represents a radical from the group (a), in which

[0048] R⁴ represents a radical of the formula

B—X²—,

[0049]  in which

[0050] B stands for C₁-C₆-Alkyl or Phenyl, whereby the Phenyl group canbe substituted by one, two or three of the groups selected from ahalogen, C₁-C₄-Alkoxy, C₁-C₄-Alkyl-SO₂—, C₁-C₅-Alkanoyl,C₁-C₄-Alkoxycarbonyl, C₁-C₄-Haloalkyl, C₁-C₄-Haloalkoxy,C₁-C₄-Alkoxy-C₁-C₄-alkyl, Carboxy, Amino, C₁-C₄-Alkylamino,Di-(C₁-C₄-alkyl)-amino, Aminosulfonyl, Phenyl and Hydroxy, or

[0051] represents a Phenyl group, in which two neighbouring carbon atomsare replaced by a C₁-C₄-Alkylene-dioxy groups

[0052] X² represents a CO, NH—CO, or a single bonding, and/or

[0053] R⁵ is hydrogen or a radical of the formula

D—(CH₂)_(t)—,

[0054]  in which

[0055] D represents C₁-C₄-Alkyl, C₃-C₆-Cycloalkyl, Phenyl, Naphthyl or a5- or 6-membered nitrogen, oxygen and/or sulphur-containing heterocyclicgroup in which the phenyl group can be substituted by one, two or threegroups selected from a halogen, C₁-C₄-Alkyl-SO₂—, C1-C4-Haloalkyl,C₁-C₄-Haloalkoxy, Aminosulfonyl, Phenyl and Hydroxy, and in which

[0056] t is 0 where D is a C₁-C₄-Alkyl group, or

[0057] t is 1 or 2 where D other than a C₁-C₄-Alkyl group.

[0058] Further favoured compounds are those of the formula I, in which

[0059] R¹ represents C₁-C₁₀-Alkyl or C₃-C₆-Cycloalkyl, which, ifrequired, can be substituted once, twice or three times by one or moremembers of the group comprising C₁-C₄-Alkoxy, Phenoxy-,C₁-C₄-Alkoxy-phenoxy, Hydroxyphenoxy, C₃-C₆-Cycloalkyl, —NH₂,—NH(C₁-C₄-Alkyl), —N(C₁-C₄-Alkyl)₂, —NH—CO—(C₁-C₄-Alkyl), —CO—NH₂,—CO—NH—(C₁-C₄-Alkyl) or —NH—CO-Benzyl, or represents

[0060] Phenyl-C₁-C₄-alkyl, in which the phenyl ring can, if required, besubstituted once, twice or three times by one or more of the radicalsC₁-C₄-Alkyl, CF₃, Fluorine, Chlorine, Bromine, COOH or COO—C₁-C₄-Alkyl,or

[0061] represents a 5- or 6-membered, saturated or unsaturatedheterocyclic group that is linked via a single bond or via a C₁-C₄alkylene bridge, and that contains one, two or three heteroatomsselected from oxygen, nitrogen and sulphur, and which may be optionallysubstituted once, twice or three times by any one or more of thefollowing radicals: C₁-C₄-alkyl, phenyl optionally substituted byC₁-C₄-alkyl, or benzyl optionally substituted by C₁-C₄-alkyl; or

[0062] said 5- or 6-membered, saturated or unsaturated heterocyclicgroup is optionally condensed via two adjacent carbon atoms with abenzene ring;

[0063] R² represents —C(═NH)NH₂ or —CH₂—NH₂;

[0064] A represents piperidine or piperazine;

[0065] R³ represents a radical selected from the Group (a), (b) and (c);

[0066] (a) is —NR⁴R¹, in which

[0067] R⁴ represents B—X², in which

[0068] B stands for C₁-C₆-alkyl, phenyl, pyridyl, naphthyl ordihydrobenzo[1,4]dioxinyl, in which the phenyl, naphthyl, benzo orpyridyl group respectively can be substituted one or more times byhalogen, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkyl-SO₂—,C₁-C₄-alkyl-PO₂—O—, C₁-C₄-alkanoyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, phenyl, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)-amino, aminosulphonyl, carboxy or hydroxy;

[0069] X² represents —CO—, —NH—CO— or a single bond,

[0070] R⁵ represents hydrogen or methyl group; or

[0071] R⁴ and R⁵ together with the nitrogen atom form a 5- or 6-membersaturated hetrocyclic group or a 9- or 10-member spiro-heterocyclicgroup, that can contain a further hetero atom selected from the groupoxygen or nitrogen, in which one or two CH₂ groups can be replaced byC═O, and, if required, by one or more of the radicals C1-C₄-alkyl,C₅-C₆-cycloalkyl, benzyl, which, if required, can be substituted byC₁-C₄-alkyl, pyridyl or phenyl, that can, if required, be substituted byC₁-C₄-alkyl, C₁-C₄-alkoxy- or hydroxy group,

[0072] (a) is —E-Phenyl, in which

[0073] E stands for —CH₂CH₂— or —CH═CH—;

[0074] (b) is Phenyl, which is substituted by one or two substituentsselected from the group comprising fluorine, chlorine, trifluoromethyl-and nitro-; if required, in the form of their tautomers, theirracemates, their enantiomers, their diastereoisomers and mixturesthereof, as well as, if required, by their pharmacologicallyunobjectionable acid addition salts.

[0075] Especially favoured are those compounds of the formula (I), inwhich

[0076] R¹ stands for unsubstituted C₁-C₁₀-alkyl or C₃-C₆-cycloalkyl, orfor a C₁-C₄-alkyl group that is substituted once or twice C₁-C₄-alkoxy,phenoxy-, C₁-C₄-alkoxy-phenoxy, hydroxyphenoxy, C₃-C₆-cycloalkyl, —NH₂,—NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, —NH—CO—(C₁-C₄-alkyl), —CO—NH₂,—CO—NH—(C₁-C₄-alkyl) or —NH—CO-Benzyl, or for

[0077] Phenyl-C₁-C₃-alkyl, in which the phenyl ring may, if required, besubstituted once or twice by C₁-C₄-alkyl, CF₃, Fluorine, Chlorine,Bromine, COOH or COO—C₁-C₄-alkyl, or for

[0078] represents a 5-, 6- or 7-membered, saturated or unsaturatedheterocyclic group that is linked via a C₁-C₃-alkylene bridge, andcontains one or two heteroatoms selected from oxygen, nitrogen andsulphur, and which is optionally substituted once or twice by any one ormore of the radicals methyl, ethyl, propyl, phenyl, methylphenyl orbenzyl, or said heterocyclic group is optionally condensed via twoadjacent carbon atoms with a benzene ring;

[0079] R² represents —C(═NH)NH₂ or —CH₂—NH₂;

[0080] A represents piperidine-1,4-diyl or Piperazine-1,4-diyl;

[0081] R³ represents a radical selected from the groups (a), (b) and(c):

[0082] (a) —NR⁴R⁵, in which

[0083] R⁴ represents C₁-C₆-alkylaminocarbonyl, phenylcarbonyl,pyridylcarbonyl, phenylaminocarbonyl ordihydrobenzo[1,4]dioxinylcarbonyl, in which each phenyl, benzo orpyridyl group can be substituted once or twice by the halogen,C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₅-alkanoyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-haloalkylthio, carboxy or hydroxy group;

[0084] R⁵ stands for hydrogen or Methyl; or

[0085] R⁴ and R⁵ together with the nitrogen atom form a 5-memberedsaturated heterocyclic group or a 9-membered spiroheterocyclic group,which can contain an additional hetero atom selected from oxygen andnitrogen, in which one or two CH₂ groups are replaced by C═O, and whichis optionally substituted by any one or more of the radicals selectedfrom: C₁-C₄-alkyl, C₅-C₆-cycloalkyl, benzyl optionally substituted byC₁-C₄-alkyl, pyridyl and phenyl optionally substituted by C₁-C₄-alkyl,C₁-C₄-alkoxy or hydroxy;

[0086] (b) —E-Phenyl, in which

[0087] E stands for —CH₂CH₂— or —CH═CH—;

[0088] (c) Phenyl, which is substituted by one or two substituentsselected from the group comprising fluorine, chlorine, trifluoromethyland nitro;

[0089] or, if required, in the form of their tautomere, racemate,enantiomere, diastereomere or mixtures thereof, or, if required, astheir pharmacologically unobjectionable acid-addition salts,

[0090] In Addition, Preferred Compounds Also Include Those of Formula(I), in Which R², R³, X¹ and A Have the Afore-mentioned Meanings, and

[0091] R¹ represents unsubstituted C₁-C₁₀-alkyl or C₃-C₆-cycloalkyl, orby C₁-C₄-alkoxy-phenoxy, hydroxy-phenoxy, C₃-C₆-cyclo-alkyl, —NH₂,—NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, —NH—CO—(C₁-C₄-alkyl), —CO—NH₂,—CO—NH—(C₁-C₄-alkyl) or C₁-C₄-alkyl-substituted by —NH—CO-benzyl, orphenyl-C₁-C₃-alkyl, whereby the phenyl ring can, if required, besubstituted once or twice by C₁-C₄-alkyl, CF₃, fluorine, chlorine,bromine, COOH or COO—C₁-C₄-alkyl groups, or represents

[0092] a heterocyclic compound that is linked via a C₁-C₃-alkylenebridge, that can, if required, by substituted once or twice by one ormore of the radicals methyl, ethyl, propyl, phenyl, methyl-phenyl- orbenzyl, and that is selected from the group pyrrole, pyrroline,pyrrolide, pyridine, piperidine, pyrimidine, piperizine, morpholine,thio-morpholine, imidazole, imidazoline, imidazolidine, pyrazole,pyrazoline, pyrazolidine, triazole, furane, tetra-hydro-furane,α-pyrane, γ-pyrane, dioxolane, tetra-hydro-pyrane, dioxane, thiophene,dihydro-thiophene, thiolane, dithiolane, oxazole, isoxazole, thiazole,isothiazole, oxadiazole, benzodioxol, benzimidazole, benzthiophene,benzfuran and indole.

[0093] Especially favoured are the compounds having the formula (I), inwhich R², R³, X¹ and A have the afore-mentioned designations, and

[0094] R¹ stands for methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, cyclopropyl, cyclopentyl or cyclohexyl, or

[0095] for a methyl-, ethyl- or propyl-group that is substituted bymethoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,methoxy-phenoxy, or

[0096] stands for benzyl that is substituted once or twice by methyl,ethyl, propyl, CF₃, fluorine, chlorine, bromine, COOH, COOMe or COOEt,

[0097] stands for phenylethyl that is substituted once or twice bymethyl, ethyl, propyl, CF₃, fluorine, chlorine, bromine, COOH, COOMe orCOOEt,

[0098] or for a heterocyclic group that is connected via a methylene-,ethylene- or propylene-bridge, and that is, if required, substitutedonce or twice by one or more of the radicals methyl, ethyl, propyl,phenyl, methyl-phenyl or benzyl, and that is selected from the grouppyrrole, pyrrolidine, pyridine, piperidine, piperazine, morpholine,furane, tetrahydro-furane, thiophene, benzodioxole and benzimidazole.

[0099] An especially favoured form of the compound are the compounds ofthe formula (I), in which R², E³, X¹ and A have the afore-mentionedmeanings, and

[0100] R¹ represents methyl, ethyl, propyl, pentyl, n-decyl, cyclopropylor cyclohexyl, or

[0101] for a methyl-, ethyl or propyl-radical that is substituted bymethoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl ormethoxy-phenoxy, or

[0102] for benzyl that is substituted by methyl, CF₃, COOH, COOMe orCOOEt, or

[0103] for tetrahydrofurane that is connected via a methylene bridge.

[0104] Further favoured compounds are those having the formula (I) inwhich R², R³, X¹ and A have the afore-mentioned meanings, and

[0105] R¹ represents methyl, ethyl, propyl, pentyl, cyclopropyl,phenyl-ethyl, phenyl-propyl, cyclopropyl-methyl,tetrahydro-furanyl-methy or benzyl, that is substituted once or twice byCF₃, COOH, COOMe or COOEt.

[0106] Most favoured compounds are those of formula (I) in which R², R³,X¹ and A have the afore-mentioned meanings especially where

[0107] R¹ is methyl or cycloprogyl. and

[0108] R² is —C(═NH)NH₂.

[0109] Most especially favoured are the compounds of the formula (IA)

[0110] in which R³ has the afore-mentioned meaning, and

[0111] G is CH or N.

[0112] Especially good results have been obtained with the compounds offormula I or IA that are selected from the group comprising

[0113][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-dihydrochloride

[0114][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazinyl]-amid-dihydrochloride

[0115][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[(2-cyclohexyl-ethyl)-piperazinyl]-amid-dihydrochloride

[0116][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(5-benzyl-2,4-dioxo-oxazolidine-3-yl)-piperidinyl]-amide-hydrochloride

[0117][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[2-benzoylamino-(2,3-dihydro-benzo[1,4]dioxine)]-piperydinyl}-amide-hydrochloride

[0118][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-oxo-3-phenyl-imidazolidine-1-yl)-piperidinyl]-amide-hydrochloride

[0119][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,4-dioxo-1-oxa-3-aza-spiro[4,4]non-3-yl)-piperidinyl]-amide-hydrochloride

[0120][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(4-fluorobenzamido)-piperazinyl]-amid-hydrochloride

[0121][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(4-nitrophenyl)-piperazinyl]-amide-dihydrochloride

[0122][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-pyridylamido)-piperidinyl]-amide-dihydrochloride

[0123][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-butyl-ureido)-piperidinyl]-amide-hydrochloride

[0124][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,4-dioxo-5-propyl-oxazolidine-3-yl)-piperidinyl]-amide-hydrochloride

[0125][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide-hydrochloride

[0126][2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic-{4-[3-(2,3-dichloro-phenyl)-ureido]-piperidinyl}-amide-hydrochloride

[0127]2-[2-(4-Aminomethylphenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamidopiperidinyl)-amide

[0128]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-(4-phenethyl-piperazinyl)-amide-dihydrochloride

[0129]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-(4-benzamidopiperidinyl)-amide-hydrochloride

[0130]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-hydrochloride

[0131]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-trihydrochloride

[0132]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-ureido)-piperidinyl]-amide-dihydrochloride

[0133]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-{4-[2-benzoylamino-(2,3-dihydro-benzo[1,4]dioxin)]-piperydinyl}-amide-dihydrochloride

[0134]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(5-benzyl-2,4-dioxo-oxazolidine-3-yl)-piperidinyl]-amide-dihydrochloride

[0135]2-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[(2-cyclohexyl-ethyl)-piperazinyl]-amide-trihydrochloride

[0136]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-chloro)-benzamidopiperidinyl)-amide

[0137]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-brom)-benzamidopiperidinyl)-amide

[0138]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-hydroxy)-benzamidopiperidinyl)-amide

[0139]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-difluoromethylsulfanyl)-benzamidopiperidinyl)-amide

[0140]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-difluoromethylsulfanyl)-benzamidopiperidinyl)-amide

[0141]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,3-dichloro)-benzamidopiperidinyl)-amide

[0142]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-methoxy)-benzamidopiperidinyl)-amide

[0143]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-bromo)-benzamidopiperidinyl)-amide

[0144]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-chloro)-benzamidopiperidinyl)-amide

[0145]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(N-methyl)benzamidopiperidinyl]-amide

[0146]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-anilinopiperidinyl)-amide

[0147]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(2,3-dichloro)-phenyl-1-methyl-ureido]piperidinyl)-amide

[0148]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-acetyl)-phenylureido]piperidinyl}-amide

[0149]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-carboxyl)-phenylureido]piperidinyl)-amide

[0150]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide

[0151]2-[2-(4-Methoxycarbonylamidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide

[0152]2-[2-(4-Isobutoxycarbonylamidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide

[0153]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methylsulfanyl)phenylureido9piperidinyl}-amide

[0154]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-iodo)-phenylureido]piperidinyl}-amide

[0155]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-chloro)-phenylureido]piperidinyl}-amide

[0156]2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)-phenyl-1-methyl-ureido]piperidinyl)-amide

[0157] if required, in the form of their tautomers, racemates,enantiomers, diastereoisomers and mixtures thereof, as well as, ifrequired, their pharmacologically unobjectionable acid addition salts.

[0158] In addition to the afore-mentioned compounds of the generalformula (I), the present invention also has the object of the productionof compounds that, in view of the transformation in vivo of thecompounds into their cleavable functionality of the therapeuticallyeffective compounds of the general formula (I) by the organs only afteringestion by the patient. Such compounds are referred to as ‘Pro-drugs’.A further object of the invention is, therefore, the poroduction ofpro-drugs of the formula (II)

[0159] in which

[0160] R¹, R³, A and X¹ have the meanings ascribed to them in the Claims1 to 11; and R⁶ stands for a radical that is split off underphysiological conditions in man or animal bodies, preferably under theinfluence of proteases, to release the corresponding compound of theformula I.,

[0161] if required, in the form of their tautomers, racemates,enantiomers or diastereoisomers or mixtures thereof, or, if required, astheir pharmacologically unobjectionable acid-addition salts.

[0162] Preferably, R⁶ represents Hydroxy, C₁-C₈-Alkoxy,—O—CO—C₁-C₈-Alkyl, O—CO—O—C₁-C₈-Alkyl, —CO—(O)_(s)—C₁-C₈-Alkyl,—CO—(O)_(s)—C₁-C₄-Haloalkyl, —CO—(O)_(s)—C₁-C₄-Alkyl-O—CO—C₁-C₄-Alkyl,—CO—(O)_(s)-Phenyl, —CO—(O)_(s)-Pyridyl,—CO—(O)_(s)—C₂-C₄-Alkenyl-Phenyl or —CO—(O)_(s)—C₁-C₄-Alkyl-Phenyl,

[0163] whereby, the phenyl ring in each of the above-named groups can besubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkylamine,di-(C₁-C₄-alkyl)-amine, C₁-C₄-alkoxy, C₁-C₄-alkanoyl, C₁-C₄-alkanoyloxyor C₁-C₄-haloalkoxy, and

[0164] s is 0 or 1, especially where

[0165] R⁶ represents hydroxy, methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, octyloxycarbonyl, 222-trichloerethoxycarbonyl,benzyloxycarbonyl, phenoxycarbonyl, methoxyphenoxycarbonyl,methylphenoxycarbonyl, acetyloxystibenylcarbonyl, especially2-(ortho-acetyloxyphenyl)-ethene-1-ylcarbonyl or Phenylcarbonyl,

[0166] if required, in the form of their tautomers, racemates,enantiomers or diastereoisomers or mixtures thereof, or, if required, astheir pharmacologically unobjectionable acid-addition salts.

[0167] In addition, the object of the present invention is to provide ause of the above-defined compounds of the general formula (I), as wellas of the pro-drugs of the general formula (II), for the production ofmedicines for the treatment of diseases, by which tryptase-inhibitorscan promote a therapeutic value.

[0168] According to the invention, the use of the afore-mentionedcompounds of the general formula (I) is preferred for the production ofmedicines for the prevention and/or treatment of inflamed and/orallergic illnesses. Especially preferred is the use of the compoundsindicated at the beginning, of the general formula (I) for theproduction of medicines for the prevention and/or treatment of bronchialasthma, allergic rhinitis, allergic conjunctivitis, atopical dermatitis,urticaria, allergic otitis, allergic stomach-intestinal illnesses,Morbus Crohn, colitis ulcerosa, anaphylactic shock, septic shock,shock-lung (ARDS) and arthritis. It is, further, of interest, to use thecompounds mentioned at the beginning, that correspond to the generalformula (I) for the production of medicines for the prevention and/ortreatment of illnesses having re-constructive antecedents in therespiratory passages and in the lung parenchyma, such as chronic(obstructive) bronchitis and interstitial lung diseases such asidiopathic lung fibrosis, fibrous alveolitis, sarcoidosis andhistio-cytosis X, as well as other fibrous diseases such as scar tissueformation, as well as collagenoses such as lupus eryhmetodis andsclerodermy, as well as arterio-sclerosis, psoriasis and neoplases.

[0169] The synthesis of aminocarbonyl-substituted benzimidazolederivatives of the formula (I), as well as those of the pro-drugs of thegeneral formula (II) is facilitated by reference to the synthesis knownfrom the prior art. In this connection, reference can be made to theinternational patent applications WO 98/37075 and WO 01/14342 referredto at the beginning, the contents of which are specifically noted atthis point.

[0170] A further aspect of the invention has as objective the compoundsof the general formula (III)

[0171] in which the radicals X¹, R¹, R³ and A can have the meanings asindicated above. The compounds of the general formula (III) representvaluable intermediary products for the production according to theinvention of aminocarbonyl-substituted benzimidazole derivatives of thegeneral formula (I), as well as of prodrugs of the invention having thegeneral formula (II).

[0172] A possible access to the compounds of the invention having theformula I through the use of conventional chemical synthetic methods isschematically presented in Scheme I:

[0173] In a first synthesising stage (Stage i), starting from4-halogen-3-nitro-benzoic acid derivatives, through aminolysis withappropriate substituted amines, the synthesis of 4-amino-3-nitrobenzoicacid derivatives can be achieved. The reaction is carried out in asuitable organic solvent such, for example, as dimethylsulphoxide,N,N-dimethylformamide, N-methylpyrrolidone or also, if desired, in Waterat room temperature or at a temperature in the range of 30-80° C.,preferably at 40-50° C. The aminobenzoic acid compounds obtained aretransferred into a corresponding alkyl ester, preferably into thecorresponding methyl ester or ethyl ester by conventional, standardmethods, (Stage ii). The reduction of the nitro group to thediaminobenzoic acid-alkyl ester is achieved, preferably, by means of acatalytic hydrogenation in accordance with Stage iii. The catalyst usedcan, preferably, be palladium. Especially preferred is the use ascatalyst of palladium on charcoal (5%). By reacting the diaminobenzoicester so obtained with p-cyanophenyl-propionic acid in the presence ofdehydrating reagents, the benzimidazole-heterocyclic compound isobtained in accordance with stage v (Scheme 1). The conversion ispreferably carried out in a solvent or mixture of solvents such, forexample, as methylenchloride, dimethylformamide, Benzene, Toluene,Chlorobenzene, tetrahydrofurane, benzene/tetrahydrofurane or dioxan. Asdehydrating agent can be considered chloro-formic acid-isobutyl ester,ortho-carbonic acid-tetraethylester, ortho-acetic acid-trimethylester,2,2-dimethoxypropane, tetramethoxysilane, phosphorus oxychloride,thionyl chloride, trimethyl chlorsilane, phosphorus trichloride,phosphorus pentoxide, 1,2-Dihydro-2-ethoxy-quinoline-1-carboxylicacid-ethylester (EEDQ), 1,2-dihydro-2-i-propyloxy-quinoline-1-carboxylicacid-i-propylester (IIDQ), N,N′-dicyclohexyl-carbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoro-borat,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoro-borate/1-hydroxy-benztriazole,N,N′-carbonyldiimidazole orTriphenylphosphine/Tetrachloro-carboxylic-carbon. If required, it may beuseful to add a base such as pyridine, 4-dimethyl-amino-pyridine,N-methyl-morpholine or triethylamine. The conversion normally takesplace at temperatures between 0 and 150° C., preferable at temperaturesbetween 0 and 110° C.

[0174] The benzimidazole derivatives of the general formula (III)obtained in accordance with Stage v are either directly obtainable fromthe above-named benzimidazole-carboxylic acid esters or by way of thecorresponding carboxylic acids or carboxylic acid halides.

[0175] In the event that the carboxylic acid esters obtained accordingto the Stage iv are saponified under standard conditions (protic organicsolvent such, for example, as methanol, ethanol or isopropanol, ifrequired in the presence of water, in the presence of bases such ashydroxides or carbonates of alkaline-or alkaline earth metals), thisleads to the corresponding free carboxylic acids. Normally, thesaponification is carried out at temperatures between 0-40° C.,preferably at 10-30° C. If required, the synthesis can also be carriedout at a raised temperature (reflux temperature>50° C.).

[0176] According to the invention, the preferred solvent is amethanol-water mixture. As the base used, sodium hydroxide is preferred.The conversion of the acids so obtained with the amines H—NR³R⁴ into thecompounds of the general formula (III) is, if desired, carried out in asolvent or solvent mixture such as methylene chloride,dimethylformamide, Benzene, Toluene, Chlorobenzene, Tetrahydrofurane,Benzene/Tetrahydrofurane or dioxane, or in the corresponding cyclicalamine of the formula

[0177] if necessary, in the presence of an dehydrating agent such, forexample, as in the presence of chloroformic acid isobutylester,ortho-carboxylic acid-tetra-ethylester, ortho-aceticacid-trimethylester, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchloro-silane, phosphor-trichloride,phosphor-pentoxide, N,N′-dicyclohexyl-carbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxy-succinimide,N,N′-Dicyclohexyl-carbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium-tetrafluoroborate,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium-tetrafluoroborate/1-hydroxy-benztriazole,N,N′-Carbonyl-diimidazole or triphenylphosphine/Tetrachloro-carbon, and,if required, with the addition of a base such as pyridine,4-dimethylamino-pyridine, N-methyl-morpholine3 or triethylamine,usefully at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C.

[0178] The synthesis of the compounds of the general formula (III)starting from the carboxylic acid esters or from the correspondingcarboxylic acid chlorides obtained in accordance with the Scheme 1(Stage iv) is either carried out in the corresponding cyclical amine ofthe formula

[0179] as solvent, or with this amine in the presence of a solvent suchas methylene chloride, ether or ethyl acetate and, preferably, in thepresence of a tertiary organic base such as triethylamine,N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between0 and 150° C., preferably at temperatures between 40 and 100° C.

[0180] A compound of the general formula (I) is, for example, obtainableby treatment of a compound of the general formula (III, Stage vi) with acorresponding alcohol such as methanol, ethanol, n-propanol, isopropanolor benzylalcohol, if desired in a mixture with another organic solventsuch, for example, as Chloroform, nitrobenzene or Toluene in thepresence of an acid such as hydrochloric acid, or by reaction of acorresponding amide with a trialkyloxonium salt such astriethyloxonium-tetrafluoroborate in a solvent such as methylenechloride, tetrahydrofurane or dioxane at temperatures between −10 and50° C., preferably, however, between 0 to 20° C. Alternatively, thecompounds of the general formula (I) can be obtained by reacting acompound of the general formula (III, Stage vi) withsulphur-nucleophiles such, for example, as hydrogen sulphide, ammonium-or sodium sulphide, sodium-hydrogen sulphide, carbon disulphide,thioacetamide or bis-trimethyl-silyl-thioether, if required in thepresence of bases such as triethylamine, ammonia, sodium-hydride orsodium-alcoholate in solvents such as methanol, ethanol, water,tetrahydro-furane, pyridine, dimethyl-formamide or1,3-dimethyl-imidazolidine-2-one, at 20-100° C., and treatment with asuitable methylating agent such, for example, as methyl iodide ordimethyl sulphate, in a solvent such as Acetonitrile or Acetone, attemperatures between −10 and 50° C., but preferably at 0-20° C., andthen treatment with ammonia, ammonium carbonate or ammonium chloride ina suitable alcohol such, for example, as methanol, ethanol, isopropanoletc. at temperatures between −10 and 50° C., but preferably at 0-20° C.

[0181] In addition, the compounds of the invention having the generalformula (I) are obtainable by treatment of a compound of the generalformula (III) with lithium-hexamethyl-disilazide in a suitable organicsolvent such, for example, as tetrahydro-furane at temperatures between−20 and 50° C., but preferably at 0-20° C., and then by hydrolysis withdiluted hydrochloric acid at 0-5° C.

[0182] A further alternative method of obtaining the compounds of thegeneral formula (I) can succeed through the treatment of a compound ofthe general formula (III) with ammonium chloride and trimethyl-aluminiumin a suitable organic solvent such, for example, as toluene, attemperatures between 20 and 150° C., but preferable at 110° C.

[0183] A compound of the general formula (II) is obtainable, forexample, by treatment of a compound of the general formula III, Stagevii) with hydroxylamine in the presence of carbonates or alcoholates ofalkali- or alkali-earth metals, in solvents such as methanol, ethanol,n-propanol or iso-propanol, if desired, in mixtures with dioxane ortetrahydro-furane. The alcoholates can be obtained from the respectivealkali metals or metal hydrides and the corresponding alcohol. Thereaction is, preferably, carried out at 20-100° C., especiallypreferably at the boiling point temperature of the solvent used.Compounds of the general formula (II) can, alternatively, be obtained bytreatment of a compound of the general formula (III, Stage vii) with acorresponding alcohol such as methanol, ethanol, n-propanol,iso-propanol or benzyl alcohol, in the presence of an acid such ashydrochloric acid, or by reaction of a corresponding amide with atrialkyl-oxonium salt such as triethyl-oxonium-tetra-fluoroborate in asolvent such as methylene chloride, tetrahydro-furane or dioxane, attemperatures between −10 and 50° C., but preferably at 0-20° C., andthen treatment with hydroxylamine in the presence of bases in a suitablealcohol such as methanol, ethanol, isopropanol, etc., at temperaturesbetween −10 and 50° C., but preferably at 0-20° C.

[0184] A compound of the general formula (I) is obtained, for example,by treatment of a compound of the general formula (II, Stage viii) withhydrogen in the presence of hydrogenating catalysts such as Raney Nickelor rhodium/aluminium oxide in water or methanol, if required, with theaddition of acids such as hydrochloric acid or methane-sulphonic acid,or by treatment with hydrogen in the presence of palladium/carbon inacetic acid/acetic anhydride at 20-50° C. and at 1-5 bar water pressure,preferably at room temperature and standard pressure.

[0185] Acyl- or alkoxycarbonyl-prodrugs of the compound having thegeneral formula (I) are obtained by reaction of compounds of the generalformula (I) with the corresponding acid chlorides in the presence ofbases such, for example, as triethylamine, N-methyl-morpholine,diethyl-isopropylamine or DBU in a suitable solvent such as methylenechloride, chloroform, tetrahydro-furane, aceto-nitrile,dimethyl-formamide or dimethyl-sulphoxide.

[0186] The following examples describe in detail methods for theproduction of the compounds according to the invention. The followingexamples of the syntheses serve exclusively as detailed illustrations,without the subject of the invention being restricted thereto.

EXAMPLE 1[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-dihydrochloride

[0187]

[0188] a) 4-Methylamino-3-nitrobenzoic acid:

[0189] 20 g (100 mmol) of 4-Chloro-3-nitro-benzoic acid is dissolved in80 ml of a 40% aqueous solution of methylamine, stirred for 15 hours atroom temperature and for 1.5 hours at 40-50° C. After cooling, it isacidified with acetic acid. The crystals formed are filtered off, washedwith cold water and dried. The yield: 18.2 g (93%); Melting point: 220°C.

[0190] b) Methylamino-3-nitro-benzoic acid-methyl ester

[0191] 9.8 g (50 mmol) of 4-methylamino-3-nitro-benzoic acid are treatedin 50 ml of dimethyl formamide (DMF) with K₂CO₃ (14 g). 5 ml of dimethylsulphate are added dropwise to this mixture over 10 minutes withstirring. It is stirred for 15 minutes and heated for 0.5 hours at 60°C. After cooling, it is diluted with water, the precipitated solids arefiltered off, washed with water and dried. Yield: 9.8 g (93%); M.Pt.:138-140° C.

[0192] c) 3-amino-4-methylamino-benzoic acid methyl ester

[0193] 71 g of 4-methylamino-3-nitro-benzoic acid-methyl ester (338mmol) are hydrogenated in 1.4 1. of methanol and 67 ml of concentratedaqueous hydrochloric acid in the presence of 15 g of Pd/C (5%) at 2-5bar, at room temperature. After filtering off the catalysts anddistilling off the solvent under vacuum, the residue is dissolved in 200ml of water, covered with ethyl acetate and basified with a 50% solutionof potassium carbonate. The product is extracted in the organic phase,which is again washed with water and then dried over sodium sulphate.After removal of most of the solvent by distillation under vacuum,diethyl ether is added and it is cooled off. The resulting crystals arefiltered off. Yield: 54 g (81%); MPt.: 215-220° C. (decomposition).

[0194] d)2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acidmethyl ester:

[0195] 7.5 g of 3-Amino-4-methylamino-benzoic acid-methylester (42 mmol)and 7.3 g p-cyano-phenyl-propionic acid (42 mmol) are dissolved in 50 mlof phosphorus oxychloride and heated under reflux for 2 hours. Aftercooling, the excess phosphorus oxychloride is treated with ice-water. Itis covered with ethyl acetate and basified with potassium carbonate,with stirring. The organic phase is separated, washed with water anddried. After distilling off most of the solvent under vacuum, it iscooled off. The precipitated crystals are filtered and washed with coldethyl acetate or diethyl ether. Yield: 8.5 g (63%). MPT.: 148-150° C.;Mass: reported: [319], found: [M+H]⁺320, [M+Na]⁺342, [2M+H]⁺639;

[0196]¹H-NMR (250 MHz, DMSO-d6): δ [ppm]=8.18 (7H, m, aryl-H); 3.86 (3H,s, OCH₃); 3.75 (3H, s, aryl-N—CH₃); 3.26 (4H, s, aryl-CH₂—CH₂—).

[0197] e)2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid

[0198] 5.0 g of2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-methyl ester (15.7 mmol) are dissolved in 50 ml of methanol,treated with 20 ml of an aqueous sodium hydroxide solution(1 N) andboiled under reflux for 0.5 hours. It is then treated with 20 ml of anaqueous solution of hydrochloric acid (1 N) and diluted with water. Theprecipitated crystals are filtered off, and washed with water, acetoneand ether. The raw product obtained is re-crystallized from dimethylformamide. Yield: 4.5 g (94%); MPt.: >220° C.

[0199] f)2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide

[0200] 0.4 g of2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid(1.3 mmol), 4-(3-phenyl-allyl)-piperazine (0.26 g, 1.3 mmol) and 0.4 mlof triethylamine are dissolved in 8 ml of dimethylformamide. 0.54 g ofO-(Benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate(═TBTU; 1.7 mmol) are added and stirred for 24 h at room temperature.After diluting with 20 ml of ethyl acetate, it is washed with saturated,aqueous sodium bicarbonate solution and with water, and dried oversodium sulphate. The solvent is boiled down and the product purifiedchromatographically (silica gel; gradient; acetic ester/methanol 100% in60% acetic ester). Yield: 0.52 g (80%); yellow oil.

[0201] g)2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amid-hydrochlorid:

[0202] 0.14 g of2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide (0.2 mmol) are added to acooled, saturated at 0° C. ethanolic solution of HCl. Stirring iscontinued until complete solution of the separated material and thetemperature held at 0-5° C. for about 12 hours. The ethanol is distilledoff at a maximum temperature of 40° C. and the residue dissolved in 30ml of an ethanolic ammonia solution saturated at 0° C. Stirring iscarried on for 1 hour at room temperature and 2 hours at 40-50° C.,treated with 10 ml of the previously described ammonia solution, boiledunder reflux for 1 hour and allowed to stand for 12 hours at roomtemperature. The precipitated inorganic salts are filtered off, thefiltrate is reduced to half its volume and then diluted with 50 ml ofacetone. The precipitated crystals are filtered off and washed withacetone. Yield: 0.15 g (25%); MPt.: >250° C.;

[0203]¹H-NMR (250 MHz, DMSO-d6): δ [ppm]=9.25; 8.86 (4H, 2 s, NH₂—C═NH₂⁺); 7.81-7.13 (12H, m, aryl-H); 6.60-6.17 (2H, m, —CH═CH—); 3.67 (3H, s,NH—CH₃—); 3.61-2.98 (14H, m/s, O═C—CH₂; aryl-CH₂—CH₂—, piperazin-CH₂—,N—CH₂—CH═CH—).

EXAMPLES 2 TO 14

[0204] The following compounds of Examples 2 to 14 are prepared in ananalogous manner to that of the description of Example 1, with thecorresponding amines (Stage f). The amine required for the preparationof the compound of Example 6 can be obtained in accordance with theGerman publication DE 2701 794. The amines required for the preparationof the compounds of the Examples 7 and 12 can be obtained in accordancewith the German publication DE 32 35 565.

2 [2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazinyl]-amide-dihydrochloride,MPt.: 216° C. 3[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[(2-cyclohexyl-ethyl)-piperazinyl]-amide-dihydrochloride, MPt.:170° C. (Decomp.) 4[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(5-benzyl-2,4-dioxo-oxazolidine-3-yl)-piperidinyl]-amide-hydrochloride,MPt: 196° C. 5[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[2-benzoylamino-(2,3-dihydro-benzo[1,4]dioxine)]-piperydinyl}-amide-hydrochlorid,MPt.: 140° C. (decomp.) 6[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-oxo-3-phenyl-imidazolidine-1-yl)-piperidinyl]-amide-hydrochloride,MPt.: 200° C. 7[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,4-dioxo-1-oxa-3-aza-spiro[4,4]non-3-yl)-piperidinyl]-amide-hydrochloride,MPt.: >250° C. 8[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(4-fluorobenzamido)-piperazinyl]-amide-hydrochloride, MPt.: 248°C. (Decomp.) 9[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(4-nitrophenyl)-piperazinyl]-amide-dihydrochloride, MPt.: 203°C. 10 [2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-pyridylamido)-piperidinyl]-amide-dihydrochloride, MPt.: 155°C. (Decomp.) 11[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-butyl-ureido)-piperidinyl]-amide-hydrochloride 12[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,4-dioxo-5-propyl-oxazolidine-3-yl)-piperidinyl]-amide-hydrochloride13 [2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide-hydrochloride 14[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(2,3-dichloro-phenyl)-ureido]-piperidinyl}-amide-hydrochlorideEXAMPLE 152-[2-(4-Aminomethylphenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide

[0205]

[0206] a)2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide:

[0207] The synthesis is carried out by starting from2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acidand by reacting this with 4-benzamidopiperidine in an analogous mannerto that of Example 1, stage f.

[0208] b)2-[2-(4-Aminomethyl-phenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide:

[0209] 2.0 g (4.1 mmol)2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide are hydrogenated in 30 ml ofmethanol in the presence of about 2 g of methanol-moist Raney Nickel atroom temperature and standard pressure. The catalyst is filtered off andwashed with methanol, and the solvent is distilled off under vacuum. Theresidue is hydrogenated over silica gel (acetic ester:methanol:ammonia,80:20:1) and then chromatographed over an RP-18 column (gradientacetonitrile:water: 0-2 min. 90% water over 11 min. of 90 to 5% water, 5min. 5% water). Yield: 0.4 g (20%); MPt.: 165-167° C.,

[0210]¹H-NMR (250 MHz, CDCl₃, TMS=0 ppm): δ [ppm]=7.80-7.12 (12H, m,aryl-H); 6.14 (1H, d, J=6.5 Hz, NH—CH); 4.60 (2H, s, wide, NH₂); 4.29(1H, m, piperidine-CH—); 3.85 (2H, s, phenyl-CH₂—N); 3.58 (3H, s,aryl-N—CH₃); 3.19 (4H, s, aryl-CH₂—CH₂—); 3.38-1.98 (8H, m,piperidine-CH₂—).

EXAMPLE 162-[2-(4-Benzoylamidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamidopiperidinyl)-amide

[0211]

[0212] a)2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide:

[0213] The synthesis, starting with2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid,follows in an analogous manner to that of Example 1, stage g.

[0214] b)2-[2-(4-Benzoylamidinomethyl-phenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide:

[0215] 1.0 g (2 mmol) of2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide and 3.2 ml Triethylamine (23 mmol)are dissolved in 10 ml of dimethyl formamide. The mixture is cooled downto 0° C. and 0.418 ml of benzoyl chloride (3.6 mmol) are slowly addeddropwise. After 2 hours 20 ml of water are added to the mixture, and theaqueous phase is extracted with 20 ml of acetic ester. The organic phaseis again washed with waterand dried over sodium sulphate. The solvent isdistilled off under vacuum. The residue is chromatographed over silicagel with acetic ester, and the oily product is triturated with petroleumether. The precipate is filtered and washed with petroleum ether. Yield:0.160 g (15%); MPt: 150-154° C.;

[0216]¹H-NMR (250 MHz, DMSO-d6): δ [ppm]=8.43 (1H, d, J=7.5 Hz, NH—CH);8.37-7.28 (19H, m, aryl-H, NH₂); 3.79 (3H, s, N—CH₃); 3.30 (4H, 2 m,aryl-CH₂—CH₂—); 4.26-1.32 (9H, m, piperidine-CH₂—CH).

EXAMPLE 172-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(2-phenyl-ethyl)-piperazinyl]-amide-dihydrochloride

[0217]

[0218] a) 4-(3-ethoxy-propyl)-3-nitrobenzoic acid:

[0219] 90 ml (0.74 mmol) of 3-ethoxy-propylamine are dissolved in 90 mlof water, and 20 g of 4-chloro-3-nitro-benzoic acid (100 mmol) are addedto it portionwise. The mixture is stirred for 24 hours at 70° C. Aftercooling, it is acidified with acetic acid. The crystals formed arefiltered off, washed with cold water and dried. Yield: 20 g (75%).

[0220] The other intermediary stages are synthesised with reference tothe procedure given in Example 1 with the 4-(2-phenyl-ethyl)-piperizine(Stage f). From 0.5 g2-[2-(4-cyanophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(2-phenyl-ethyl)-piperazinyl]-amide, 0.32 mg (62%) of crystalsare obtained.

[0221]¹H-NMR (250 MHz, DMSO-d6): δ [ppm]=9.30; 9.05 (4H, 2 s, NH₂—C═NH₂⁺); 7.81-6.98 (12H, m, aryl-H); 4.25-1.78 (24H, m, 2×(aryl-CH₂—CH₂—),N—(CH₂)₃—O—CH₂), -piperazine-CH₂); 1.07 (3H, t, J=6.7 Hz, —O—CH₂ CH₃ .

EXAMPLES 18 TO 23

[0222] The compounds of the Examples 18 to 23 are produced in ananalogous manner to that described in Example 17, with the correspondingamines (Stage f). The amine required for the production of the compoundof Example 22 can be obtained in accordance with the German publicationDE 32 35 565.

182-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide-hydrochloride, MPt.: >250° C. 192-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-hydrochloride, MPt.: 238° C.(Decomp.) 202-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazol-5-yl-carbonsäure-[4-(3-phenyl-ureido)-piperidinyl]-amid-dihydrochlorid,Schmp.: 235° C. (Decomp.) 212-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazol-5-yl-carboxylicacid-{4-[2-benzoylamino-(2,3-dihydro-benzo[1,4]dioxin)]-piperydinyl}-amide-dihydrochloride,MPt.: 230° C. (Decomp.) 222-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(5-benzyl-2,4-dioxo-oxazolidine-3-yl)-piperidinyl]-amide-dihydrochloride,MPt.: 185° C. (Decomp.) 232-[2-(4-Amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[(2-cyclohexyl-ethyl)-piperazinyl]-amide-trihydrochloride, MPt.:240° C. (Decomp.) EXAMPLE 24[2-(4-Amidinophenyl)-ethyl-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(2,3-dichloro-phenyl)-ureido]-piperidinyl}-amide-hydrochloride

[0223]

[0224] a) 1-(2,3-Dichloro-phenyl)-3-piperidine-4-yl-urea:

[0225] 0.66 g (3.3 mmol) of 4-Amino-piperidine-1-carboxylic acidtert-butyl ester are dissolved in 30 ml of dichloroethane, treated with3.3 mmol of 2,3-dichlorophenyl isocyanate and stirred at roomtemperature for 3 hours. In order to complete the reaction, it is heatedat 50° C. for 4 hours. It is then treated with 2.5 ml of trifluoroaceticacid at room temperature and then allowed to stand for 24 hours. Thesolvent is distilled off under vacuum, and the product is immediatelyreacted further under b). Yield of a yellowish solid: 1.3 g, HPLC-MS,purity: 98% (reported: 287; found: [M+H]+288; column: Waters XTerra,C18MS, 4.6×50, 3.51 μm; solvent A: Water (0.1% TFA), solvent B:Acetonitrile (0.1% TFA), gradient: 95% A to 98% B in 5 min., flow rate:1 ml/min.

[0226] b) Linkage in an analogous manner with the benzimidazole buildingblock as in Example 1 (Stage f)

EXAMPLES 25 TO 63

[0227] The compounds of the Examples 25 to 63 are prepared in ananalogous manner as described in Example 24, using the correspondingamines (Stage f). Ret. Time* [M + H]⁺ [min.] 254-(2-{1-Methyl-5-[4-(3-m-tolyl-ureido)-piperidine-1- [538] 3.18carbonyl]-1H-benzimidazole-2-yl}-ethyl)-benzamidine 264-[2-(5-{4-[3-(3-Fluoro-phenyl)-ureido]-piperidine-1- [542] 3.17carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 274-[2-(5-{4-[3-(2-Fluoro-phenyl)-ureido]-piperidine-1- [542] 3.03carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 284-[2-(5-{4-[3-(3-Methoxy-phenyl)-ureido]-piperidine-1- [554] 3.02carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 294-[2-(5-{4-[3-(2-Chloro-phenyl)-ureido]-piperidine-1- [558] 3.21carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 304-[2-(5-{4-[3-(2-Methoxy-phenyl)-ureido]-piperidine-1- [554] 4.9**carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 314-[2-(5-{4-[3-(4-Chloro-phenyl)-ureido]-piperidine-1- [558] 3.33carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 324-[2-(1-Methyl-5-{4-[3-(3-trifluoromethyl-phenyl)-ureido]- [592] 3.48piperidine-1-carbonyl}-1H-benzimidazole-2-yl)-ethyl]- benzamidine 334-[2-(5-{4-[3-(2,4-Difluoro-phenyl)-ureido]-piperidine-1- [560] 3.12carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 344-(2-{1-Methyl-5-[4-(3-naphthalen-1-yl-ureido)-piperidine-1- [574] 3.26carbonyl]-1H-benzimidazole-2-yl}-ethyl)-benzamidine 354-[2-(5-{4-[3-(2,4-Dichloro-phenyl)-ureido]-piperidine-1- [592] 5.66**carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 364-(2-{1-Methyl-5-[4-(3-naphthalen-2-yl-ureido)-piperidine-1- [574]5.49** carbonyl]-1H-benzimidazole-2-yl}-ethyl)-benzamidine 374-[2-(5-{4-[3-(2-Bromo-phenyl)-ureido]-piperidine-1- [602] 3.22carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 384-[2-(5-{4-[3-(2,6-Difluoro-phenyl)-ureido]-piperidine-1- [560] 4.45**carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 394-[2-(5-{4-[3-(4-Bromo-phenyl)-ureido]-piperidine-1- [602] 3.37carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 404-(2-{5-[4-(3-Cyclohexyl-ureido)-piperidine-1-carbonyl]-1- [530] 4.76**methyl-1H-benzimidazole-2-yl}-ethyl)-benzamidine 414-[2-(1-Methyl-5-{4-[3-(4-trifluoromethyl-phenyl)-ureido]- [592] 5.67piperidine-1-carbonyl}-1H-benzimidazole-2-yl)-ethyl]- benzamidine 424-[2-(5-{4-[3-(4-Fluoro-phenyl)-ureido]-piperidine-1- [542] 3.06carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 434-[2-(5-{4-[3-(3-Bromo-phenyl)-ureido]-piperidine-1-carbonyl}-1-methyl-1H-benzimidazole-2-yl)-ethyl]- benzamidine 442-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(3-chloro)-benzamidopiperidinyl)-amide 452-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(3-bromo)-benzamidopiperidinyl)-amide 462-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(2-hydroxy)-benzamidopiperidinyl)-amide 472-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(2-difluoromethylsulfanyl)- benzamidopiperidinyl)-amide 482-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(3-difluoromethylsulfanyl)- benzamidopiperidinyl)-amide 492-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(2,3-dichloro)- benzamidopiperidinyl)-amide 502-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(2-methoxy)-benzamidopiperidinyl)-amide 512-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(2-bromo)-benzamidopiperidinyl)-amide 522-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-[4-(2-chloro)-benzamidopiperidinyl)-amide 532-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carbooxylicacid-[4-(N-methyl)benzamidopiperidinyl]-amide 542-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-(4-anilinopiperidinyl)-amide 552-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(2,3-dichloro)-phenyl-1-methyl-ureido] piperidinyl)-amide 562-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(3-acetyl)-phenylureido] piperidinyl}-amide 572-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(3-methoxycarbonyl) phenylureido]piperidinyl}-amide 582-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(3-methylsulfanyl)phenylureido] piperidinyl}-amide 592-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(3-iodo)-phenylureido] piperidinyl}-amide 602-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(3-chloro)-phenylureido] piperidinyl}-amide 612-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl- carboxylicacid-{4-[3-(3-methoxycarbonyl)-phenyl-1-methyl-ureido]piperidinyl)-amide

EXAMPLE 62[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-carboxyphenyl)-ureido]-piperidinyl}-amide

[0228]

[0229] 0.3 g (0.48 mmol) of2-[2-(4-Amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide (Example57) are dissolved in 5 ml of methanol and treated with 1.2 ml of 2Ncaustic soda solution and allowed to stand for 5 hours at roomtemperature. It is then treated with 0.1 ml of acetic acid and dilutedwith water. The precipitate is filtered off under suction and washedwith water. 0.2 g of a white solid is obtained. MPt: 231-235° C.

EXAMPLES 63-201

[0230] The compounds listed in the following Tables I to IV are preparedin an analogous manner to that described in the previous Example. TABLEI

R⁴ 63 3-Chloro-6-propylphosponyloxybenzoyl 64 2,5-Dichlorobenzoyl 652,3-Dichlorophenyl 66 Naphth-1-yl 67 2,3-Dichlorobenzoyl

[0231] TABLE II

B R⁵ 68 3-Mehoxycarbonylphenyl Methyl 69 4-Chlorophenyl H 704-Chlorophenyl 4-Methanesulfonyl-benzyl 71 4-ChlorophenylPyrid-2-ylmethyl 72 4-Chlorophenyl 4-Bromobenzyl 73 4-Chlorophenyl4-Benzenesulfonamide- methyl 74 Phenyl H 75 Phenyl4-Methanesulfonylbenzyl 76 4-Chlorophenyl Prop-2-in-1-yl 774-Cyanophenyl Pyrid-2-ylmethyl 78 4-Chlorophenyl3-Trifluoromethoxybenzyl 79 4-Chlorophenyl 1-Naphthalin-1-ylmethyl 80Phenyl Pyrid-2-ylmethyl 81 Phenyl 4-Bromobenzyl 82 4-Chlorophenyl2-(Pyrrolidin-1-yl)-ethyl 83 4-Chorophenyl Pyrid-3-ylmethyl 84 Phenyl3-Trifluoromethoxybenzyl 85 4-Chlorophenyl 2,2,2-Trifluoroethyl 864-Chlorophenyl Methyl 87 Phenyl Naphthalin-1-ylmethyl 881,1′-Biphenyl-4-yl 3-(Morpholino-1-yl)-propyl 89 4-Chlorophenyl2-(Thien-2-yl)-ethyl 90 4-Chlorophenyl 3,5-Bis-trifluoromethyl- benzyl91 Phenyl 3,5-Bis-trifluoromethyl- benzyl 92 4-ChlorophenylPyrid-4-ylmethyl 93 4-Chlorophenyl (4-Benzenesulfonamidyl)- methyl 94Phenyl (4-Benzenesulfonamidyl)- methyl 95 4-ChlorophenylCyclopropyl-methyl 96 4-Cyanophenyl 4-Bromobenzyl 97 1,1′-Biphenyl-4-ylPyrid-3-ylmethyl 98 4-Cyanophenyl (4-Benzene- sulfonamidyl)methyl 994-Chlorophenyl 3-Ethoxypropyl 100 4-Chlorophenyl3-(Morpholino-1-yl)-propyl 101 Phenyl 2,2,2-Trifluoroethyl 1021,1′-Biphenyl-4-yl 4-Bromobenzyl 103 4-Cyanophenyl4-Methanesulfonyl-benzyl 104 4-Cyanophenyl 3,5-Bis-trifluoromethyl-benzyl 105 Propionyl Naphthalin-1-ylmethyl 106 Phenyl Pyrid-4-ylmethyl107 Phenyl Prop-2-in-1-yl 108 Propionyl H 109 Phenyl2-(Thien-2-yl)-ethyl 110 4-Cyanophenyl Pyrid-4-ylmethyl 1114-Cyanophenyl 3-Trifluoromethoxy-benzyl 112 Phenyl Pyrid-3-ylmethyl 113Phenyl Methyl 114 4-Cyanophenyl 3-(Morpholino-1-yl)-propyl 1154-Chlorophenyl 3-(Pyrrolidin-2-on-1-yl)- propyl 116 PhenylCyclopropyl-methyl 117 4-Cyanophenyl Naphthalin-1-ylmethyl 1181,1′-Biphenyl-4-yl 3,5-Bis-trifluoromethyl- benzyl 119 4-Cyanophenyl2,2,2-Trifluorethyl 120 4-Cyanophenyl 2-(4-Benzenesulfonamidyl)- ethyl121 Phenyl 2-(4-Benzenesulfonamidyl)- ethyl 122 Phenyl3-(Pyrrolidin-2-on-1-yl)- propyl 123 4-Cyanophenyl Cyclopropyl-methyl-124 Phenyl 3-(Morpholino-1-yl)-propyl 125 4-CyanophenylPyrid-3-ylmethyl- 126 Phenyl 3-Ethoxypropyl 127 4-Cyanophenyl2-(Pyrrolidin-1-yl)-ethyl 128 1,1′-Biphenyl-4-yl 2-(Thien-2-yl)-ethyl129 4-Cyanophenyl Methyl 130 Propionyl 4-Bromobenzyl 1311,1′-Biphenyl-4-yl 3-Ethoxypropyl 132 4-Cyanophenyl3-(Pyrrolidin-2-on-1-yl)- propyl 133 4-Cyanophenyl H 134 Propionyl3-Trifluoromethoxy-benzyl- 135 Phenyl 2-(Pyrrolidin-1-yl)-ethyl- 1361,1′-Biphenyl-4-yl 3-(Pyrrolidin-2-on-1-yl)- propyl 1371,1′-Biphenyl-4-yl 2-(Pyrrolidin-1-yl)-ethyl 138 1,1′-Biphenyl-4-yl3-Trifluoromethoxy-benzyl 139 Propionyl 4-Methanesulfonyl-benzyl 1404-Cyanophenyl 3-Ethoxypropyl 141 1,1′-Biphenyl-4-yl Pyrid-4-ylmethyl 142Propionyl 3,5-Bis-trifluoromethyl- benzyl 143 PropionylCyclopropyl-methyl 144 Propionyl Prop-2-in-1-yl 145 1,1′-Biphenyl-4-yl2-(4-Benzenesulfonamidyl)- ethyl 146 Propionyl (4-Benzenesulfonamidyl)-methyl 147 1,1′-Biphenyl-4-yl Methyl 148 1,1′-Biphenyl-4-yl4-Methanesulfonyl-benzyl 149 1,1′-Biphenyl-4-yl H 150 1,1′-Biphenyl-4-yl(4-Benzenesulfonamidyl)- methyl 151 Propionyl 2-(Thien-2-yl)-ethyl 152Propionyl Pyrid-4-ylmethyl 153 Propionyl 2-(Pyrrolidin-1-yl)-ethyl 154Propionyl Methyl 155 Propionyl Pyrid-2-ylmethyl 156 1,1′-Biphenyl-4-ylPyrid-2-ylmethyl 157 1,1′-Biphenyl-4-yl 2,2,2-Trifluoroethyl- 1581,1′-Biphenyl-4-yl Prop-2-in-1-yl 159 Propionyl Pyrid-3-ylmethyl 160Propionyl 2-(4-Benzenesulfonamidyl)- ethyl 161 Propionyl 3-Ethoxypropyl162 Propionyl 3-(Pyrrolidin-2-on-1-yl)- propyl 163 Propionyl3-(Morpholino-1-yl)-propyl 164 Benzenesulfonyl- H 165 Propionyl2,2,2-Trifluoroethyl

[0232] TABLE III

R⁴ R⁵ 166 (E)-2-Phenyl-ethen-1-sulfonyl Methyl 167(E)-2-Phenyl-ethen-1-sulfonyl H 168 Butan-1-sulfonyl Methyl 169Naphthalene-1-ylsulfonyl Methyl 170 3-Chloro-2-methyl-benzene-1- Methylsulfonyl 171 2,3-Dichlorobenzene-1-sulfonyl Methyl 1723-Nitrobenzene-1-sulfonyl H 173 Butane-1-sulfonyl H 1743-Chlorobenzene-1-sulfonyl Methyl 175 3-Bromobenzene-1-sulfonyl Methyl176 Naphthalene-1-ylsulfonyl H 177 5-Dimethylamino-naphthalene-1- Methylylsulfonyl 178 Benzenesulfonyl Methyl 179 5-Dimethylamino-naphthalene-1-H ylsulfonyl 180 3-Chloro-2-methyl-benzene-1- H sulfonyl 1812,5-Dichlorobenzene-1-sulfonyl Methyl 182 3-Nitrobenzene-1-sulfonylMethyl 183 3-Chlorobenzene-1-sulfonyl H 184 3-Bromobenzene-1-sulfonyl H185 2,5-Dichlorobenzene-1-sulfonyl H 186 2,3-Dichlorobenzene-1-sulfonylH 187 3-Trifluoromethylbenzene-1-sulfonyl Methyl- 1883-Trifluoromethylbenzene-1-sulfonyl H 189 2-(Naphthalene-1-yl)-acetyl H

[0233] TABLE IV

R⁴ 190 2-Fluoroanilinocarbonyl 191 3-Methoxyanilinocarbonyl 1922-Chloroanilinocarbonyl 193 3-Chloroanilinocarbonyl 1943-Bromoanilinocarbonyl 195 2,3-Dichloroanilinocarbonyl 196 Benzoyl 1973-Chlorobenzoyl 198 3-Bromobenzoyl 199 3-Iodobenzoyl 2003-Methylsulphonylbenzoyl 201 2,3-Dichlorobenzoyl

[0234] The compounds of the invention are notable for their effectivetrypsin-inhibiting property. The said capacity to inhibit trypsinactivity was determined in accordance with the following trialdescriptions.

[0235] The determinations are carried out in tris-HCl buffer (100 mM),that also contained calcium (5 mM) and heparin (100 mg/ml), at a pH of7.4. As the standard, rh beta trypsin is used, this is commerciallyobtainable, for example, from Promega. A suitable substrate isN-p-Gly-Pro-Lys-para-nitroaniline in a concentration of 0.6 mM. Thesubstrate is digested with trypsin, whereby p-nitro-aniline is obtainedthat can be measured at 405 nm. Normally, an incubation period of 5minutes and an incubation temperature of 37° C. is chosen. For theenzyme activity, 0.91 U/ml are used. The determination is carriedout inan auto-analyser (Cobas Bio) from the firm Hoffmann LaRoche. Thepotential inhibitor substances are used in the screening procedure inconcentrations of 10 μM , and the inhibition of the trypsin is given inpercentages. At an inhibition in excess of 70%, the IC₅₀ is determined(the concentration at which 50% of the enzyme activity is inhibited).After a 5-minute pre-incubation of the potential inhibiting substance,the substrate is added for the start of the reaction, whereby theproduction of p-nitro-aniline is taken, after 5 minutes, after testingthe linearity, as a measure of the enzyme activity.

[0236] The following Table V contains the results obtained from in vitrotests of the compounds of the invention having the formula I. Thesymbols are: +++ IC50: 0.0001-0.0010 μM ++ IC50: 0.0010-0.0200 μM +IC50: 0.0200-0.0500 μM

[0237] TABLE V Example Trypsin-inhibiting property 1 ++ 2 ++ 3 ++ 4 ++ 5++ 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 ++ 12 ++ 13 ++ 14 +++ 15 ++ 17 + 18 ++19 ++ 20 ++ 21 ++ 22 ++ 23 ++ 24 +++ 25 ++ 26 ++ 27 +++ 28 +++ 29 +++ 30++ 31 ++ 32 ++ 33 ++ 34 ++ 35 ++ 36 ++ 37 +++ 38 ++ 39 ++ 40 ++ 41 ++ 42++ 43 +++ 44 +++ 45 +++ 46 ++ 49 ++ 50 ++ 53 ++ 55 ++ 56 ++ 57 ++ 58 +++60 +++ 61 ++ 62 ++ 63 ++ 64 +++ 65 ++ 66 ++ 67 +++ 68 + 69 ++ 70 ++ 71++ 72 ++ 73 ++ 74 ++ 75 ++ 76 ++ 77 ++ 78 ++ 79 ++ 80 ++ 81 ++ 82 ++ 83++ 84 ++ 85 ++ 86 ++ 87 ++ 88 ++ 89 ++ 90 ++ 91 ++ 92 ++ 93 ++ 94 ++ 95++ 96 ++ 97 ++ 98 ++ 99 ++ 100 ++ 101 ++ 102 ++ 103 ++ 104 ++ 105 ++ 106++ 107 ++ 108 ++ 109 ++ 110 ++ 111 ++ 112 ++ 113 ++ 114 ++ 115 ++ 116 ++117 ++ 118 ++ 119 ++ 120 ++ 121 ++ 122 + 123 + 124 + 125 + 126 + 127 +128 + 129 + 130 + 131 + 132 + 133 + 134 + 135 + 136 + 137 + 138 + 139 +140 + 141 + 142 + 143 + 144 + 145 + 146 + 147 + 148 + 149 + 166 ++ 167++ 168 ++ 169 ++ 170 ++ 171 + 173 + 189 ++ 196 +

[0238] The following Table VI contains the results of the in vitro testscarried out on the pro-drugs of the invention of the formula IIA TABLEVI (IIA) Prodrug R⁶ IC50 [μM] IIA1  OH 3.66 IIA2  OCO-Phenyl 3.16 IIA3 OCOO-Methyl 5.18 IIA4  O-Methyl 37.5 IIA5  COO-Methyl 0.09 IIA6 COO-Ethyl 2.49 IIA7  COO-n-Propyl 4.02 IIA8  COO-n-Pentyl 5.8 IIA9 COO-n-Hexyl 5.62 IIA10 COO-n-Octyl 7.91 IIA11 COO-i-Propyl 4.39 IIA12COO-tert-Butyl 3.46 IIA13 COO-2,2,2-Trichloroethyl 2.53 IIA14 COO-Benzyl0.12 IIA15 COO-4-Methoxyphenyl 0.16 IIA16 COO-4-Methylphenyl 0.06 IIA17CO-Phenyl 0.36 IIA18 OCO-Methyl 4.16 IIA19 COO—CH(Methyl)—O—CO— 0.40IIA20 CO—CH═CH-(ortho-Acetoxyphenyl) 0.098

[0239] The trypsin-inhibitors of the invention can be administeredorally, trans-dermally, by inhalation or parenterally. The compounds ofthe invention comprise the active ingredients in standard forms ofadministration such, for example, as in compositions that are,substantially, made up of an inert pharmaceutical carrier with aneffective dosage of the active ingredient such, for example, as tablets,pills, capsules, wafers, powders, solutions, suspensions, emulsions,syrups, suppositories, transdermal systems, etc. An effective dosage ofthe compounds of the present invention would be, in the case of an oralform, between 1 and 100, preferably between 1 and 50, especiallypreferably between 5 and 30 mg/dose; in the case an intra-venous orintramuscular administration, it would be between 0.001 and 50,preferably between 0.1 and 10 mg/dose. For inhalation, the solutions ofthe invention would suitably contain 0.01 to 1.0, preferably 0.1 to 0.5%of active ingredient. For the inhalative administration, the use ofpowders is preferred. In addition, it is possible to administer thecompounds of the invention in the form of infusion solutions, preferablyin a physiological cooking salt solution or nutritional salt solution.

[0240] The compounds of the invention may be administered separately orin combination with other active ingredients of the invention, ifrequired, in combination with other pharmacologically activeingredients. Suitable administrative forms are, for example, tablets,capsules, plugs, solutions, juices, emulsions or dispersible powders.Appropriate tablets can, for example, be based on mixtures of this orthese active ingredients with known carriers such, for example, as inertdiluents such as calcium carbonate, calcium phosphate or lactose,disintegrating agents such, for example, as maize starch or algin acid,binding agents such as starch or gelatine, lubricants such as magnesiumstearate or talc, and/or agents for providing a sustained release actionsuch as carboxy-methyl cellulose, cellulose acetate-phthalate, orpolyvinyl acetate. The tablets can also consist of several layers.

[0241] Appropriately, pills can be prepared by coating tablets, that areprepared analogously as kernels, with, normally, pill-coating materialssuch, for example, as collidon or varnish, gum arabica, talc, titaniumdioxide or sugar. For providing a sustained release action, or toprevent incompatibilities, the kernels can also comprise several layers.Similarly, the pill coating can comprise a number of layers forachieving a depot action, whereby the carrier substances referred toabove in connection with the tablets, can be incorporated.

[0242] Juices containing the active ingredients of the invention, orcombinations of active ingredients, can additionally contain asweetening agent such as saccharine, cyclamate, glycerine or sugar, aswell as a taste-improving substance such, for example, as aromasubstances such as vanilla- or orange-extract. They can, in addition,contain suspension-promoting agents or thickeners such as sodiumcarboxy-methyl cellulose, or wetting agents such, for example, ascondensation products of aliphatic alcohols with ethylene oxide, orprotective substances such as p-hydroxy-benzoate.

[0243] Injectable solutions are usually prepared, for example, with theaddition of preserving agents, such as p-hydroxy-benzoates, orstabilizers, such as alkali salts of ethylene-diamine-tetraacetic acid,and filled into injection phials or ampoules.

[0244] The capsules that contain one or more active ingredients orcombinations of ingredients can, for example, be prepared by mixing theactive ingredients with inert carriers such as lactose or sorbitol andencapsulating in gelatine capsules.

[0245] Suitable plugs can be prepared, for example, by mixing withspecially prepared carriers, such as neutral fats or polyethyleneglycol, or derivatives thereof.

[0246] A therapeutically effective daily adult dose is between 1 and 800mg, preferably 10-300 mg.

[0247] The following examples illustrate the present invention without,however, thereby restricting its scope.

[0248] Examples of Pharmaceutical Formulations A) Tablets per TabletActive ingredient 100 mg Lactose 140 mg Maize starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg 500 mg

[0249] The finely ground active ingredient, the lactose and a part ofthe maize starch are mixed together. The mixture is sieved, thenmoistened with a solution of polyvinyl pyrrolidone in water, kneaded,moist-granulated and dried. The granulate, the remaining maize starchand the magnesiuym stearate are sieved and mixed together. The mixtureis then pressed into a suitable form and size of tablet. B) Tablet perTablet Active ingredient 80 mg Maize starch 190 mg Lactose 55 mgMicro-crystalline cellulose 35 mg Polyvinyl pyrrolidone 15 mg Sodiumcarboxymethyl starch 23 mg Magnesium stearate 2 mg 400 mg

[0250] The finely ground active ingredient, a part of the maize starch,the lactose, the micro-crystalline cellulose and the polyvinylpyrrolidone are mixed together, the mixture is sieved and worked withthe remaining part of the maize starch and water into a granulate, whichis dried and sieved. The sodium carboxymethyl starch and the magnesiumstearate are added and the mixture is pressed into tablets of a suitablesize. C) Pills Per Pill Active ingredient 5 mg Maize starch 41.5 mgLactose 30 mg Polyvinyl pyrrolidone 3 mg Magnesium stearate 0.5 mg 80 mg

[0251] The active ingredient, the maize starch, the lactose and thepolyvinyl pyrrolidone are well mixed together and moistened with water.The moist mass is pressed through a sieve having a 1 mm mesh size, driedat 45° C. and the granulate is then mashed through the same sieve. Afteradding and mixing the magnesium stearate, it is pressed in a tablettingmachine into dished pills having a diameter of 6 mm. The pills obtainedare then coated by a known method with a layer that substantiallycomprises sugar and talc. The finished pills are polished with wax. D)Capsules per Capsule Active ingredient 50 mg Maize starch 268.5 mgMagnesium stearate 1.5 mg 320 mg

[0252] The substance and the maize starch are mixed together andmoistened with water. The moist mass is sieved and dried. The driedgranulate is sieved and mixed with the magnesium stearate. The finalmixture is filled into hard-gelatine capsules, size 1. E) AmpoulleSolution Active ingredient 50 mg Sodium chloride 50 mg Aqua pro inj. 5ml

[0253] The active ingredient is dissolved in water at its own pH or, ifdesired, at a pH between 5.5 and 6.5, and treated with isotonic sodiumchloride. The solution obtained is filtered pyrogen-free and thefiltrate is filled under aseptic conditions into ampoules that are thensterilized and heat sealed. The ampoules contain 5 mg, 25 mg and 50 mgof active ingredient. (F) Suppositories Active ingredient 50 mg Adepssolidus 1650 mg 1700 mg

[0254] The hard fat is melted. The milled active ingredient mixture isdispersed to a homogeneous mass at 40° C. It is cooled to 38° C. andmoulded into slightly cooled suppository shapes.

We claim:
 1. A compound of the formula (I):

wherein: R¹ represents C₁-C₁₀-alkyl or C₃-C₆-cycloalkyl, each optionallysubstituted once, twice or three times by any one or more of thefollowing groups: C₁-C₄-alkoxy, phenoxy, hydroxyphenoxy,C₁-C₄-alkoxy-phenoxy, C₃-C₆-cycloalkyl, —NH₂, —NH(C₁-C₄-alkyl),—N(C₁-C₄-alkyl)₂, —NH—CO—(C₁-C₄-alkyl), —CO—NH₂, —CO—NH—(C₁-C₄-alkyl) or—NH—CO-benzyl, or represents phenyl-C₁-C₄-alkyl, in which the phenylring may be optionally substituted once, twice or three times by any oneor more of the following radicals: C₁-C₄-alkyl, CF₃, fluorine, chlorine,bromine, COOH or COO—C₁-C₄-alkyl, or represents a 5-, 6- or 7-membered,saturated or unsaturated heterocyclic group that is linked via a singlebond or via a C₁-C₄-alkylene bridge, and that contains one, two or threeheteroatoms selected from oxygen, nitrogen and sulphur, and which may beoptionally substituted once, twice or three times by any one or more ofthe following radicals: C₁-C₄-alkyl, phenyl optionally substituted byC₁-C₄-alkyl, or benzyl optionally substituted by C₁-C₄-alkyl; or said5-, 6- or 7-membered, saturated or unsaturated heterocyclic group isoptionally condensed via two adjacent carbon atoms with a benzene ring;R² is —C(═NH)NH₂ or —CH₂—NH₂; X¹ is —CO—; A represents a 4- to7-membered, saturated heterocyclic group that contains one or twonitrogen atoms and optionally one or two heteroatoms selected fromoxygen and sulphur; R³ represents a radical selected from the groups(a), (b) and (c): (a) is —NR⁴R⁵; in which R⁴ is hydrogen or a radical ofthe formula: B—(CH₂)_(r)—X²—  wherein: B represents a C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₃-C₈-cycloalkyl, phenyl, naphthyl or a 5- or 6-membered nitrogen-,oxygen- and/or sulphur-containing heterocyclic group, in which thephenyl, naphthyl or heterocyclic group can be substituted by any one ormore groups selected from halogen, nitro, cyano, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-alkyl-SO₂—, C₁-C₄-alkyl-PO₂—O—,C₁-C₅-alkanoyl, C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-haloalkylthio, C₁-C₄-cyanoalkyl, C₁-C₄-hydroxyalkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, carboxy, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)-amino, aminosulfonyl, phenyl and hydroxy, or Brepresents a phenyl group in which two adjacent carbon atoms are jointlysubstituted by a C₁-C₄-alkylenedioxy; X² represents CO, NH—CO, SO₂,NH—SO₂, or a single bond, and r is 0 or a whole number from 1 to 4, R⁵represents hydrogen or a radical of the formula D—(CH₂)_(t)—,  in whichD represents C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₈-cycloalkyl, phenyl, naphthyl or a 5- or6-membered nitrogen-, oxygen- and/or sulphur-containing heterocyclicgroup, in which each phenyl, naphthyl or heterocyclic group can besubstituted by any one or more of the groups selected from: halogen,nitro, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio,C₁-C₄-alkyl-SO₂—, C₁-C₄-alkyl-PO₂—O—, C₁-C₅-alkanoyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy,C₁-C₄-haloalkylthio, C₁-C₄-cyanoalkyl, C₁-C₄-hydroxyalkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, carboxy, amino, C₁-C₄-alkylamino,di-(C₁-C₄-alkyl)-amino, aminosulphonyl, phenyl and hydroxy, or Drepresents a phenyl group, in which two adjacent carbon atoms arejointly substituted by C₁-C₄-alkylenedioxy; and t is 0 or a whole numberfrom 1 to 4; or R⁴ and R⁵ together with the nitrogen atom form a 4- to10-membered, saturated heterocyclic group or spiro-heterocyclic group,which can optionally contain a further hetero atom selected from oxygen,nitrogen and sulphur, in which one or two CH₂ groups can be replaced byC═O or C═S, and which may be substituted by any one or more of theradicals selected from: C₁-C₄-alkyl, C₃-C₈-cycloalkyl, benzyl optionallysubstituted by C₁-C₄-alkyl, pyridyl and phenyl optionally substituted byC₁-C₄-alkyl, C₁-C₄-alkoxy or hydroxy; (b) is —E-phenyl, in which Estands for —CH₂CH₂— or —CH═CH—; (c) is phenyl, which is substituted byany one or more substituents selected from halogen, trifluoromethyl andnitro; or a tautomer, racemate, enantiomer, diastereoisomer or mixturethereof, or a pharmacologically unobjectionable acid-addition saltthereof.
 2. A compound of the formula (I) as claimed in claim 1,wherein: R³ reprersents a radical of group (a), in which R⁴ is asdefined in claim 1, and R⁵ is hydrogen or D—(CH₂)_(t)—, in which Drepresents C₁-C₄-alkyl, C₃-C₆-cycloalkyl, phenyl, naphthyl or a 5- or6-membered nitrogen-, oxygen- and/or sulphur-containing heterocyclicgroup, in which the phenyl group can be optionally substituted by anyone, two or three groups selected from halogen, C₁-C₄-alkyl-SO₂—,C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, aminosulphonyl, phenyl and hydroxy,and t is 0 if D is a C₁-C₄-alkyl group, or t is 1 or 2, if D is otherthan a C₁-C₄-alkyl group.
 3. A compound of the formula (I) as claimed inclaim 1, wherein R¹ represents C₁-C₁₀-alkyl or C₃-C₆-cycloalkyl, whichcan be optionally substituted once, twice or three times by any one ormore of the following groups: C₁-C₄-alkoxy, phenoxy-,C₁-C₄-alkoxy-phenoxy, hydroxyphenoxy, C₃-C₆-cycloalkyl, —NH₂,—NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, —NH—CO—(C₁-C₄-alkyl), —CO—NH₂,—CO—NH—(C₁-C₄-alkyl) or —NH—CO-benzyl, or represents phenyl-C₁-C₄-alkyl,in which the phenyl ring can be optionally substituted by any one ormore of the following radicals: C₁-C₄-alkyl, CF₃, fluorine, chlorine,bromine, COOH or COO—C₁-C₄-alkyl, or represents a 5- or 6-membered,saturated or unsaturated heterocyclic group that is linked via a singlebond or via a C₁-C₄ alkylene bridge, and that contains one, two or threeheteroatoms selected from oxygen, nitrogen and sulphur, and which may beoptionally substituted once, twice or three times by any one or more ofthe following radicals: C₁-C₄-alkyl, phenyl optionally substituted byC₁-C₄-alkyl, or benzyl optionally substituted by C₁-C₄-alkyl; or said 5-or 6-membered, saturated or unsaturated heterocyclic group is optionallycondensed via two adjacent carbon atoms with a benzene ring; R²represents —C(═NH)NH₂ or —CH₂—NH₂; A represents piperidine orpiperazine; R³ represents a radical selected from the group (a), (b) and(c): (a) —NR⁴R⁵; in which R⁴ stands for B—X²— in which B is C₁-C₆-alkyl,phenyl, pyridyl, naphthyl or dihydrobenzo[1,4]dioxinyl, whereby eachphenyl, naphthyl, benzo or pyridyl group can be substituted by one ormore groups selected from: halogen, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-alkyl-SO₂—, C₁-C₄-alkyl-PO₂—O—, C₁-C₄-alkanoyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, phenyl, amino,C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)-amino, aminosulfonyl, carboxy andhydroxy; X² represents —CO—, —NH—CO— or a single bond, R⁵ representshydrogen or methyl, or R⁴ and R⁵ together with the nitrogen atom form a5- or 6-membered, saturated heterocyclic group, or a 9- or 10-memberedspiroheterocyclic group, which can contain a further hetero atomselected from oxygen and nitrogen, in which one or two CH₂ groups can bereplaced by C═O, and can be optionally substituted by any one or more ofthe radicals: C₁-C₄-alkyl, C₅-C₆-cycloalkyl, benzyl optionallysubstituted by C₁-C₄-alkyl, pyridyl and phenyl optionally substituted byC₁-C₄-alkyl, C₁-C₄-alkoxy or hydroxy; (b) —E-phenyl, in which E is—CH₂CH₂— or —CH═CH—; (c) phenyl substituted by any one or twosubstituents selected from: fluorine, chlorine, trifluoromethyl andnitro; or a tautomer, racemate, enantiomer, diastereoisomer or mixturethereof, or a pharmacologically unobjectionable acid-addition saltthereof.
 4. A compound of the formula (I), as claimed in claim 1,wherein: R¹ represents an unsubstituted C₁-C₁₀-alkyl or C₃-C₆-cycloalkylgroup, or a C₁-C₄-alkyl group that is substituted once or twice byC₁-C₄-alkoxy, phenoxy-, C₁-C₄-alkoxy-phenoxy, hydroxyphenoxy,C₃-C₆-cycloalkyl, —NH₂, —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂,—NH—CO—(C₁-C₄-alkyl), —CO—NH₂, —CO—NH—(C₁-C₄-alkyl) or —NH—CO-benzyl, orrepresents phenyl-C₁-C₃-alkyl, in which the phenyl ring is optionallysubstituted once or twice by C₁-C₄-alkyl, CF₃, fluorine, chlorine,bromine, COOH or COO—C₁-C₄-Alkyl, or represents a 5-, 6- or 7-membered,saturated or unsaturated heterocyclic group that is linked via aC₁-C₃-alkylene bridge, and contains one or two heteroatoms selected fromoxygen, nitrogen and sulphur, and which is optionally substituted onceor twice by any one or more of the radicals methyl, ethyl, propyl,phenyl, methylphenyl or benzyl, or said heterocyclic group is optionallycondensed via two adjacent carbon atoms with a benzene ring; R²represents —C(═NH)NH₂ or —CH₂—NH₂; A represents piperidine-1,4-diyl orpiperazine-1,4-diyl; R³ represents a radical selected from the group(a), (b) and (c): (a) is —NR⁴R⁵; in which R⁴ representsC₁-C₆-alkylaminocarbonyl, phenylcarbonyl, pyridylcarbonyl,phenylaminocarbonyl or dihydrobenzo[1,4]dioxinylcarbonyl, in which eachphenyl, benzo or pyridyl group can be substituted once or twice byhalogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₅-alkanoyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, carboxy orhydroxy; R⁵ represents hydrogen or methyl; or R⁴ and R⁵ together withthe nitrogen atom form a 5-membered saturated heterocyclic group or a9-membered spiroheterocyclic group, which can contain an additionalhetero atom selected from oxygen and nitrogen, in which one or two CH₂groups are replaced by C═O, and which is optionally substituted by anyone or more of the radicals selected from: C₁-C₄-alkyl,C₅-C₆-cycloalkyl, benzyl optionally substituted by C₁-C₄-alkyl, pyridyland phenyl optionally substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy orhydroxy; (b) is —E-Phenyl, in which E represents —CH₂CH₂— or —CH═CH—;(c) is phenyl substituted by one or two substituents selected fromfluorine, chlorine, trifluoromethyl and nitro; or a tautomer, racemate,enantiomer, diastereoisomer or mixture thereof, or a pharmacologicallyunobjectionable acid-addition salt thereof.
 5. A compound of the formula(I) as claimed in claim 1, wherein: R¹ represents unsubstitutedC₁-C₁₀-alkyl, C₃-C₆-cycloalkyl or C₁-C₄-alkyl that is substituted byC₁-C₄-alkoxy, phenoxy, C₁-C₄-alkoxy-phenoxy, hydroxyphenoxy,C₃-C₆-cycloalkyl, —NH₂, —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂,—NH—CO—(C₁-C₄-alkyl), —CO—NH₂, —CO—NH—(C₁-C₄-alkyl) or —NH—CO-benzyl, orphenyl-C₁-C₃-alkyl, in which the phenyl ring can be substituted byC₁-C₄-alkyl, CF₃, fluorine, chlorine, bromine, COOH or COO—C₁-C₄-alkyl,or R¹ represents a heterocyclic group linked via a C₁-C₃-alkylenebridge, wherein said heterocyclic group is selected from: pyrrol,pyrroline, pyrrolidine, pyridine, piperidine, pyrimidine, piperazine,morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine,pyrazole, pyrazoline, pyrazolidine, triazole, furane, tetrahydrofurane,α-pyrane, γ-pyrane, dioxolan, tetrahydropyrane, dioxane, thiophene,dihydrothiophene, thiolane, dithiolane, oxazole, isoxazole, thiazole,isothiazole, oxadiazole, benzodioxole, benzimidazole, benzthiophene,benzfurane and indole, and wherein said heterocyclic group is optionallysubstituted once or twice by any one or more of the radicals: methyl,ethyl, propyl, phenyl, methylphenyl or benzyl.
 6. A compound of theformula (I) as claimed in the claim 1, wherein: R¹ represents methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,cyclopropyl, cyclopentyl or cyclohexyl, or a methyl, ethyl or propylradical, each substituted by methoxy, ethoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, methoxyphenoxy, —NH₂, —NH(C₁-C₄-alkyl),—N(C₁-C₄-alkyl)₂, —NH—CO-methyl, —CO—NH₂, —CO—NH-methyl or—NH—CO-benzyl, or R¹ represents benzyl that is once or twice substitutedby methyl, ethyl, propyl, CF₃, fluorine, chlorine, bromine, COOH, COOMeor COOEt, or R¹ represents phenylethyl that is once or twice substitutedby methyl, ethyl, propyl, CF₃, fluorine, chlorine, bromine, COOH, COOMeor COOEt, or R¹ represents a heterocyclic group that is linked via amethylene, ethylene or propylene bridge, wherein said heterocyclic groupis selected from pyrrol, pyrrolidine, pyridine, piperidine, piperazine,morpholine, furane, tetrahydrofurane, thiophene, benzodioxole andbenzimidazole, and wherein said heterocyclic group ais optionallysubstituted once or twice by any one or more of the radicals: methyl,ethyl, propyl, phenyl, methylphenyl or benzyl.
 7. A compound of theformula (I) as claimed in claim 1, wherein: R¹ represents methyl, ethyl,propyl, pentyl, n-decyl, cyclopropyl or cyclohexyl, or a methyl, ethylor propyl radical, each substituted by methoxy, ethoxy, cyclopropyl,cyclopentyl, cyclohexyl, phenyl or methoxyphenoxy, or R¹ representsbenzyl substituted once or twice by methyl, CF₃, COOH, COOMe or COOEt,or R¹ represents tetrahydrofuran that is linked via a methylene bridge.8. A compound of the formula (I) as claimed in claim 1, wherein: R¹ ismethyl, ethyl, propyl, pentyl, cyclopropyl, phenylethyl, phenylpropyl,cyclopropylmethyl, tetrahydrofuranylmethyl, or benzyl that is once ortwice substituted by CF₃, COOH, COOMe or COOEt.
 9. A compound of theformula (I) as claimed in claim 1, wherein: R¹ is methyl or cyclopropyl.10. A compound of the formula (I) as claimed in claim 1, wherein: R¹ ismethyl or cyclopropyl; and R² is —C(═NH)NH₂.
 11. A compound according toclaim 1 having the formula (IA):

wherein R³ is as defined in claim 1, and G is CH or N.
 12. A compound ofthe formula I according to claim 1 selected from the followingcompounds:[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amid-dihydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazinyl]-amide-dihydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[(2-cyclohexyl-ethyl)-piperazinyl]-amide-dihydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(5-benzyl-2,4-dioxo-oxazolidine-3-yl)-piperidinyl]-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[2-benzoylamino-(2,3-dihydro-benzo[1,4]dioxine)]-piperydinyl}-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-oxo-3-phenyl-imidazolidine-1-yl)-piperidinyl]-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,4-dioxo-1-oxa-3-aza-spiro[4,4]non-3-yl)-piperidinyl]-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(4-fluorobenzamido)-piperazinyl]-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(4-nitrophenyl)-piperazinyl]-amide-dihydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-pyridylamido)-piperidinyl]-amide-dihydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-butyl-ureido)-piperidinyl]-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,4-dioxo-5-propyl-oxazolidine-3-yl)-piperidinyl]-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamido-piperidinyl)-amide-hydrochloride[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(2,3-dichloro-phenyl)-ureido]-piperidinyl}-amide-hydrochloride2-[2-(4-aminomethylphenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-(4-phenethyl-piperazinyl)-amide-dihydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-(4-benzamidopiperidinyl)-amide-hydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-hydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-allyl)-piperazinyl]-amide-trihydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[4-(3-phenyl-ureido)-piperidinyl]-amide-dihydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-{4-[2-benzoylamino-(2,3-dihydro-benzo[1,4]dioxin)]-piperydinyl}-amide-dihydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carbooxylicacid-[4-(5-benzyl-2,4-dioxo-oxazolidin-3-yl)-piperidinyl]-amide-dihydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-(3-ethoxy-propyl)-benzimidazole-5-yl-carboxylicacid-[(2-cyclohexyl-ethyl)-piperazinyl]-amide-trihydrochloride2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(3-chloro)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carbooxylicacid-[4-(3-brom)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-hydroxy)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-difluoromethylsulfanyl)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carbooxylicacid-[4-(3-difluoromethylsulfanyl)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2,3-dichloro)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-methoxy)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carbooxylicacid-[4-(2-brom)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(2-chloro)-benzamidopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-[4-(N-methyl)benzamidopiperidinyl]-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-(4-anilinopiperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(2,3-dichloro)-phenyl-1-methyl-ureido]piperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-acetyl)-phenylureido]piperidinyl}-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-carboxyl)-phenylureido]piperidinyl)-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide2-[2-(4-methoxycarbonylamidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide2-[2-(4-isobutoxycarbonylamidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)phenylureido]piperidinyl}-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methylsulfanyl)phenylureido]piperidinyl}-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-iodo)-phenylureido]piperidinyl}-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-chloro)-phenylureido]piperidinyl}-amide2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylicacid-{4-[3-(3-methoxycarbonyl)-phenyl-1-methyl-ureido]piperidinyl)-amide13. A compound of the formula (II)

wherein R¹, R³, A and X¹ are as defined in claim 1, and R⁶ representshydroxy, C₁-C₈-alkoxy, —O—CO—C₁-C₈-alkyl, O—CO—O—C₁-C₈-alkyl,—CO—(O)_(s)—C₁-C₈-alkyl, —CO—(O)_(s)—C₁-C₄-haloalkyl,—CO—(O)_(s)—C₁-C₄-alkyl-O—CO—C₁-C₄-alkyl, —CO—(O)_(s)-phenyl,—CO—(O)_(s)-pyridyl, —CO—(O)_(s)—C₂-C₄-alkenyl-phenyl or—CO—(O)_(s)—C₁-C₄-alkyl-phenyl, whereby each of the phenyl rings in theafore-mentioned groups can be optionally substituted by halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkylamine, di-(C₁-C₄-alkyl)-amine,C₁-C₄-alkoxy, C₁-C₄-alkanoyl, C₁-C₄-alkanoyloxy or C₁-C₄-haloalkoxy, ands is 0 or 1, or a tautomer, racemate, enantiomer, diastereoisomer ormixture thereof, or a pharmacologically unobjectionable acid-additionsalt thereof.
 14. A compound of the formula (II) as claimed in claim 13,wherein R⁶ represents hydroxy, methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, butyloxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, octyloxycarbonyl, 222-trichloroethoxycarbonyl,benzyloxycarbonyl, phenoxycarbonyl, methoxyphenoxycarbonyl,methylphenoxycarbonyl, acetyloxystilbenylcarbonyl or phenylcarbonyl, ora tautomer, racemate, enantiomer, diastereoisomer or mixture thereof, ora pharmacologically unobjectionable acid-addition salt thereof.
 15. Acompound of the formula (III)

wherein R¹, R³, A and X¹ are as defined in claim
 1. 16. A method ofpreventing or treating a disease that is preventable or treatable byinhibiting trypsin in a patient, comprising adminstering to said patientan effective amount of a compound of formula (I) according to claim 1.17. A method of treating or preventing bronchial asthma, allergicrhinitis, allergic conjunctivitis, atopical dermatitis, urticaria,allergic otitis, allergic stomach-intestinal illnesses, Morbus Crohn,colitis ulcerosa, anaphylactic shock, septic shock, shock-lung (ARDS),arthritis, chronic (obstructive) bronchitis,interstitial lung diseases,idiopathic lung fibrosis, fibrous alveolitis, sarcoidosis,histio-cytosis X, scar tissue formation, collagenoses, lupuseryhmetodis, sclerodermy, arteriosclerosis, psoriasis or neoplases in apatient, comprising adminstering to said patient an effective amount ofa compound of formula (I) according to claim
 1. 18. A method ofpreventing or treating a disease that is preventable or treatable byinhibiting trypsin in a patient, comprising adminstering to said patientan effective amount of a compound of formula (II) according to claim 13.19. A method of treating or preventing bronchial asthma, allergicrhinitis, allergic conjunctivitis, atopical dermatitis, urticaria,allergic otitis, allergic stomach-intestinal illnesses, Morbus Crohn,colitis ulcerosa, anaphylactic shock, septic shock, shock-lung (ARDS),arthritis, chronic (obstructive) bronchitis,interstitial lung diseases,idiopathic lung fibrosis, fibrous alveolitis, sarcoidosis,histio-cytosis X, scar tissue formation, collagenoses, lupuseryhmetodis, sclerodermy, arteriosclerosis, psoriasis or neoplases in apatient, comprising adminstering to said patient an effective amount ofa compound of formula (II) according to claim
 13. 20. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 1and at least one pharmaceutically acceptable carrier.
 21. Apharmaceutical composition comprising a compound of formula (II)according to claim 13 and at least one pharmaceutically acceptablecarrier.